Hello and welcome to my Karthus guide!
I am a mid Platinum EUW/EUNE player and I've made this guide for all my fellow Karthus enthusiasts. Karthus was my first champ that cost more than 450 IP and I've been maining him since I was lvl 15. I've been playing League since the start of S4 and have climbed from Bronze IV to Gold V in about 6 months during S4. In S5 I took a break from this game but have started playing again in the August of this year. I've created a new Karthus one trick account on EUNE where I reached my current mid Plat rank in about 100 ranked games played.

I've created this guide because I saw that there were no decent S7 ones on the site. I think Karthus is one of the most underrated champions in the game. Players generally dismiss him as either too boring due to a slow laning phase or as a PRESS R TO WIN GGEZ one trick champ. This guide was made so that we would have some more Karthus players in this game.

I have to apologize for my weak English skills. English is not my first language so my vocabulary/grammar might not be on the level of some of the more refined guides on this site. If you see some spelling mistakes that really bother you then please leave a comment or send me a message and I'll do my best to fix it.

I will keep updating this guide throughout the next season (as long as I don't lose interest in the game) and as I keep getting better in the game. For now consider this guide to be in a beta stage.

Pros: -Requires a somewhat different playstyle -Easy to farm with Lay Waste -Amazing passive -Can "gank" by using Requiem -Incredible AoE damage in the mid and late game -Enemies will sometimes rage when you press R

Cons: -Requires a somewhat different playstyle -Has no mobility -Weak early game -No hard CC -Teammates will sometimes rage if you pick him top

DEATH DEFIED

Upon taking fatal damage, Karthus remains active for 7 seconds, rendering himself unable to move, to use basic attacks, or to use item actives/passives, but becoming untargetable and invulnerable for the duration as well as being able to use abilities at no cost.

- Death Defied is THE spell that defines Karthus' playstyle. It is because of this passive that Karthus requires a different approach than with other mid mage champions.

-In the early game this passive can get you a kill in a duel or if the enemy jungler ganks.

-This ability allows you to play a lot more agressively in teamfights since you deal the same amount of damage in this passive as you were alive. When a teamfight happens I usually wait for someone with hard CC to engage. Immediately after that I go straight into the enemy team (using Flash if i can). When I'm about to die i pop my Zhonya's Hourglass and when they finally kill me I'm still able to do damage to the whole enemy team for 7 seconds!

- Death Defied lasts 7 seconds. Lay Waste cooldown (without cooldown reduction) is 1 second. Requiem cooldown (without CDR) is 3 seconds. This means that ideally you should use your q 4 times and then ult. Just to be safe I generally try to use q 3 times, then ult and if I have time left I use 1 more q.

-When in Death Defied mode spells don't cost any mana to use. This means that if you run out of mana in a teamfight it is often better to die so you can deal additional damage through the passive.

-If you are in your lane with no mana and low hp, the enemy laner is nowhere near and you see enemies with very low HP you can try to run under the enemy turret to execute yourself. Spells in Death Defied cost no mana so you can ult the enemy to get the kill.

- Guardian Angel will proc before Death Defied. Zilean's ult will proc before too.

-Death Defied still counts as being (kind of) alive. This means that the death timer won't be 7 seconds lower. So the amount of time before you respawn = 7 seconds + death timer

-At lvl 1 before you get your first point in Defile if you die Defile will not trigger.

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LAY WASTE

Karthus detonates the target area in the cursor's direction after a 0.5 seconds delay, dealing magic damage to all units within, doubled when hitting only a single target.

This is both your main farming tool and your main damage dealing ability through the early game.

-It deals double damage if you hit a single target. The ap ratio scaling is also doubled (0.6 instead of 0.3).

-At level 1 Karthus outtrades almost anyone due to the fact that this spell only has a 1 second cooldown. What i like to do is only use my autoattack for the 1st wave while spamming q on the enemy. I can generally deal quite a lot of damage to the enemy before he even reaches lvl 2.

-To maximize your Lay Waste damage try to hit the enemy champion just as he is about to last hit a minion. He won't be able to to dodge it if timed just right.

-In teamfights try to use Lay Waste on enemy squishies. You can usually 3 or 4 shot an enemy Lux or Ashe if you manage to actually hit them.

-With 3 points in Lay Waste you can kill enemy caster minions in 4 qs, with 4 points in 3 qs and with 5 points either in 2 or 3 qs (depending on your ap)

-Lay Waste gives vision in a small radius so use it to scout bushes.

-Lay Waste has a different sound effect when it hits a single target.

-Don't forget that it takes a while to truly become good at using q. Just keep practicing and you'll get there!

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WALL OF PAIN

Karthus creates a wall at the target location for 5 seconds. For the duration, the wall grants Sight icon sight around it, and units who cross it are both Slow icon slowed (reduced by 50% after 1 second and decaying over 4) and lose 15% magic resistance for yet the same duration.

This is your slow and your only form of (soft) CC.

-Wall of Pain costs 100 mana which is insanely expensive. Early game you should try not to spam this spell too much and should only use it either for escape, during a duel or in a trade if you know you can follow it up with at least 2 or 3 qs afterward.

-Don't forget - the spell reduces magic resist of the enemies by 15%. This is something that should never be underestimated as together with Void Staff and Piercing Thoughts this means a 57% magic resist reduction.

-Wall of Pain gives you vision and as such is perfect for checking drake/baron if you are out of wards.

- Banshee's Veil, Spell Shield and Shroud of Darkness will not block the spell.

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DEFILE

TOGGLE OFF: Karthus restores mana whenever he kills a unit.
TOGGLE ON: Karthus deals magic damage per second to all nearby units.

Your main source of damage in mid/late game teamfights.

-If toggled off it restores mana any time you kill a minion. This is the reason Karthus can last hit using Lay Waste. It also gives you mana if you lasthit a minion with your auto attack so you can esentially get free mana this way. It does not, however, give you mana if you kill a minion with Defile turned on.

-You can use it to last hit creeps by toggling the ability on for 1 second then toggling the ability off (although you won't get the mana)

-Deals negligible damage while costing a ton of mana early game. Try to use it as little as possible early on.

-It automatically toggles on when Death Defied activates.

-In teamfights try to maximize the damage dealt with Defile. You can do it by forcing fights in tight places (in jungle) and flashing in the middle of the enemy team.

- Banshee's Veil, Spell Shield and Shroud of Darkness will not block the spell.

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REQUIEM

Karthus channels for 3 seconds and deals magic damage to all enemy champions upon its completion.

Karthus' most iconic ability. A channeled global spell that deals massive damage on the entire enemy team.

-With 1 point in Requiem you can generally kill all enemies with HP lower than 200. With 2 points you can kill enemies with HP lower than 400 (if they don't stack magic resist).

-The ability is channeled - which means it can be interrupted by stuns, displacements, taunts, fears, charms etc. Be careful where you decide to cast it.

-If the ability is canceled by the enemy spell you will not get any cooldown reduction.

-At lvl 1 with no CDR it has a 200 second cooldown (3 minutes 20 seconds). This means that you have to make every cast count. Do NOT use it unless you are 90% sure you or your teammate can get a kill.

-Do not be afraid to use it however - if you see for example that your botlane is going to get a kill with the help of your ult then don't hesitate to use it.

-Do NOT use it steal a guaranteed kill from your ally.

-In teamfights it is generally best to use it after you die and enter your Death Defied passive. You can cast it before the teamfight starts but that might be blocked by a spell or an item.

- Requiem requires for you to constantly keep track of the enemy team's HP bars. This takes a bit of time to get used to but it will improve your map awareness in general.

-Enemies might buy an item like Zhonya's Hourglass or Banshee's Veil to counter your ult. When they do you should try to keep track of the cooldowns on the items. If you can you should force them to use those items before you cast your ult.

-Don't rely too much on teammates if they tell you to ult an "almost dead" enemy. This is especially true for lower leagues.

GOOD

Flash is the spell that you should take every game. End of discussion. It not only gives you a nice escape (which Karthus lacks), but is also incredible for engaging with. Generally to win teamfights you will have to deal your AoE damage on as many enemies as you can and flash will allow you to get right in the middle of the enemy team. You will be able to kill the carries with your Q while deal damage to everyone else with your E.


Exhaust is the spell I almost always take if I go Karthus mid. It not only massively reduces the damage output of the enemy, but also slows them for 2.5 seconds, thus making it considerably easier to land your Q.


I usually use Teleport when I'm playing Karthus top as it allows me to get to base, heal, buy items and return to lane without missing almost any creeps.

OK

Ignite is generally an inferior choice to exhaust on Karthus as it doesn't give a slow that would let you burst down enemies with your Q. In certain matchups, however, it is a better choice - if you are playing vs a Dr. Mundo or Volibear top for example.

DON'T TAKE

NOT SURE

I've honestly never run Cleanse on Karthus so I can't really comment on its usefulness (although it seems like a decent pick in very unique situations).


Running Ghost on Karthus might be OK, but it's only because ghost as a spell is in a good place at the moment, not because it would work all that well with Karthus.

vs
Deathfire Touch is a better mastery in my opinion. It scales better into the lategame and the damage from it is applied with every cast of your spells. Thunderlord's Decree is generally better for champs who can make use of the strong early game burst that the mastery gives. I think 18/12/0 masteries on Karthus are the way to go.

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vs
I think this one is self explanatory

vs vs
Feast is the clear winner here as it gives you early game survivability. Fresh Blood is useless on Karthus and Expose Weakness isn't really that good on AP carries in general.

vs
This one is up to you. I personally use Natural Talent , but if you feel you need some aditional sustain along with Catalyst of Aeons, Feast and Secret Stash then go for it.

vs vs

My favorite of the three is Bounty Hunter followed by Double Edged Sword and lastly Battle Trance but I think all of the three are viable.

vs
Obvious.

And lastly Deathfire Touch because it gives the most damage out of all the keystones.

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vs
Savagery is better in my opinion since it helps with the clear and last hitting.

vs vs
I've seen people run Runic Affinity on midlane champs before but I don't like taking it because you never know what kind of a jungler you're going to get... On the other hand I think both Secret Stash and Assassin work quite well so it's up to personal preference. If you need sustain then go for Secret Stash but keep in mind that Assassin does sometimes help a bit with getting that tiny bit of damage on the opponent with your ult.

vs
To me Merciless is the clear winner as 5% extra damage truly makes a difference when using your ult on an opponent with low HP. It often can mean the difference with getting kill or not. With that said I can also see why someone would want Meditation as Karthus is a mana hungry champ. Meditation definitely isn't bad, it's just that in my opinion merciless is better.

vs vs

Dangerous Game is by far the best one of the three.

STANDARD

This is the standard rune page for mid lane mages and it is what I use for Karthus on mid and sometimes top. It offers some nice protection with scaling HP and magic resist as well as damage through magic penetration and AP. It's a good page for both early game and later stages of the game as things like MPen and magic resist are needed at all stages of the game. The 15 AP from quints not only gives you that extra little bit of damage in trades, but also helps you clear a lot better early on.

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ARMOR

orThe first set of runes is what i use vs dangerous AD champs (like Zed or Talon) it allows me to keep the scaling HP seals which I think are quite useful on any mage.
The second set is the standard one that is generally used against AD assassins. It is just as good as the first set so just pick one you like more.
For top lane I often still pick the standard runes (without armor) vs some AD champs but only if I know the champion I'm playing against isn't as dangerous early game.

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COOLDOWN REDUCTION

I have used this set before as it gives you a nice 15% CDR at lvl 18. Now CDR is generally not used on Karthus as his Defile doesn't benefit from it and his Lay Waste has only a 1 second cooldown already. CDR is mostly used to bring the cooldown of Karthus' Requiem down so you can use it more frequently in the lategame. Together with Zhonya's Hourglass you will have 25% CDR at lvl 18 which brings the total cooldown down to 120 seconds (from 160). This is great as it allows you to use your ult in pretty much every lategame teamfight and it therefore increases your damage output considerably.
The tradeoff with this runepage is that you don't get the usual magic resist which makes your already weak laning phase even weaker. To offset this you can switch 3/6/9 cdr glyphs for 1/2/3 cdr quint although this reduces your starting AP by 5/10/15 which means weaker trades and weaker clear.
This runepage is definitely interesting to use and I will keep experimenting with CDR Karthus in the future. As I learn the intricacies of the playstyle a bit better I will update this part of the guide.

STARTING ITEMS

These items are a standard start for Karthus mid/top as they give sustain through Doran's Ring passive and pots, some survivability and damage through the Ring's extra HP and AP.
Selling Doran's Ring: if you have no space in your inventory you might consider selling your ring. I often see players selling the ring to buy an Amplifying Tome. This is inefficient as the Tome only gives 20 AP while the Ring gives 15 AP + 60 HP + a useful passive. I'd advise you to sell the Ring only if you need space for a bigger item that gives better overall stats than the ring.

1st ITEM: Rod of Ages vs Archangel's Staff

Both of these items are great for Karthus as each of them gives him mana, a lot of AP and HP/shield.
But let's first look at the components that we use to build these items. Rod of Ages is built from Catalyst of Aeons and Blasting Wand. The Catalyst gives 225HP and 300 mana. It also has a nice passive which restores your HP and mana as you use your spells and trade with your enemy. For 1100 gold the item is well worth its price.
Archangel's Staff is built from the Tear of the Goddess and Needlessly Large Rod. The Tear gives 250 mana and a passive that refunds 20% mana spent, effectively making your spells 20% cheaper to use. Its passive also gives 4 permanent mana for every time you use a spell. It also only costs 750 gold. On the first glance this actually looks like a great item. The problem for me is that it doesn't give you any health or sustain. It also takes very long to charge it to 750 mana. On top of that to upgrade to Archangel's Staff you still have to spend 2350 gold, a massive early game investment for an item that doesn't give any health upfront.
So all in all I have to say I prefer Rod of Ages since it gives HP and mana upfront, it gives some nice sustain to help you through the early game and the component it's built from ( Catalyst of Aeons) is better. Overall it's also cheaper so you can build Rylai's Crystal Scepter or Zhonya's Hourglass sooner.
Lastly let's look at another possibility - building BOTH RoA and Archangel's. The reason Karthus has a strong mid game is his powerspike he gets when finishing his 2nd, 3rd and 4th item (not counting boots). Karthus simply becomes a beast when he gets either Rylai's or Zhonya and can win teamfights pretty much on his own. Building Archangel as a 2nd item will weaken your general powerspike as Archangel (when not fully charged) doesn't bring any utility or survivabilty and in return it only offers ~50 extra AP. Getting Archangel also means you can't take an item you usually would as it would take that extra item slot. This generally means you wouldn't be able to buy Rabadon's Deathcap, thus actually reducing your overall damage dealt. So overall I wouldn't recommend taking both RoA and Archangel.

2nd ITEM: BOOTS

Sorcerer's Shoes are generally my boots of choice. The choice for this is obvious as Karthus needs MPen at all stages of the game.
Other boots that i would use are Mercury's Treads. These could work very well if you have a dangerous AP enemy champ ( Syndra, LeBlanc, Akali etc.) but you don't want to go along the Negatron Cloak --> Abyssal Mask build path. Personally i don't use these boots all that much though as Abyssal in general is still a good item on Karthus and if i need Magic Resist I rather get Abyssal.
Boots of Swiftness look like they might be useful aswell but I personally cannot comment on them as I have honestly never used them on Karthus.
Ionian Boots of Lucidity don't seem all that great as you can simply get CDR from runes if you really want it and I would say MPen overall is better on Karthus.

WARDS

Always remeber to buy a Control Ward on your 1st back! Whenever that ward is killed you should buy a new one so you have at least some vision around the river. Also try to ask at least the jungler to buy a Control Ward aswell.
I like taking Farsight Alteration with Karthus as facechecking bushes later on can mean your death.

3rd ITEM

Zhonya's Hourglass is a phenomenal item for any champ that deals massive AoE damage ( Fiddlesticks, Kennen, Morgana etc.). As such it also works great on Karthus. I usually take it as a 2nd item in 2 cases: if they have dangerous AD champs ( Zed, Rengar etc.) or if I want to play very aggressively. Zhonya allows you to flash right in the middle of the enemy team, use the active and be invincible for 2.5 seconds while dealing massive damage with your Defile, then land a couple of Qs on their AD and AP carries until the enemy team kills you, then enter Death Defied for 7 seconds, land 3 more Qs on their squishies and ult. If you do this right I guarantee that you will win pretty much every teamfight you enter.

Rylai's Crystal Scepter is a phenomenal item on Karthus as it gives him everything he needs. This item will allow you to chain Lay Waste on your enemies and perma slow them if you catch them out of position. In a teamfight you will be able to impair the movement of pretty much every enemy player if your positioning is on point. In addition to the slow it also gives both HP and AP. This will allow you to play more aggressively in teamfights (but not as aggressively as you would if you had Zhonya!).

In the build section above I listed Abyssal Mask as a situational item. Even though I normally prefer Rylai's or Zhonya I think Abyssal as a 3rd item is still very much viable.
I get Abyssal Mask in 2 cases: if I have a dangerous AP opponent on the lane ( LeBlanc, Syndra, Fizz etc.) or if the enemy has a heavy AP composition.
Don't be afraid to build a Negatron Cloak early on if you are very afraid of the enemy mid/top laner's burst as 720 gold is still a small investment compared to getting killed over and over. If I'm facing a dangerous enemy laner I'll usually build Negatron Cloak after I get Catalyst of Aeons and I generally finish Abyssal Mask as a second item (after I finish RoA).
Incase the enemy laner is not as dangerous but the enemy team in general has a strong AP composition (for example, I played a game vs a support Annie, Kennen top and Orianna mid) an Abyssal for a 2nd or 3rd big item is pretty much necessary. In cases like this I'd recommend finishing RoA then going Negatron Cloak --> Fiendish Codex --> Abyssal Mask.

4th & 5th ITEM

Void Staff gives you 35% MPEN. Together with Piercing Thoughts and Wall of Pain you will have 57% MPEN. you should also have ~23 flat MPEN from boots and runes. All of this MPen will allow you to basically do near true damage on any champ without Magic Resist. A champion with 200 Magic Resist will have their resist reduced to ~60. So I think it goes without saying that Void Staff is well worth the gold and I build is as a third item in 80% of cases.
Rabadon's Deathcap is a pretty straightforward item. It gives you AP and a lot of it. I generally build it as a 4th item because before you don't have enough AP to make it all that cost efficient. This item can however be delayed if you need to build something like Abyssal Mask first.

6th ITEM

I usually take either Zhonya's Hourglass, Rylai's Crystal Scepter or Liandry's Torment.

Liandry is generally useful if they have a lot of very tanky champs with lost of HP and Magic Resist as the item gives 15 flat MPen and a passive that deals 3 or 6% of the enemy's HP in damage when you use an ability. I don't know how it stacks with Deathfire Touch and will update when I figure it out.

I sometimes switch Sorcerer's Boots for Luden's Tempest at the late stages of the game as they give a similar amount of movement speed. It depends on a game to game basis whether this is worthwhile though.

SITUATIONAL ITEMS

Morellonomicon in general is not that good of an item for Karthus (at least with a build that I use). Karthus is a champion that need a big mana pool and mana regen is not as great on him. The cooldown reduction is also not as useful on him as it is on some other mages. The only reasons to buy this item are 100 AP (which is great to have) and grievous wounds. So I would only suggest getting Morello if the enemy has a lot of heals ( Soraka) or massive health regen ( Dr. Mundo). Even then I'd suggest you to take Ignite instead of Exhaust and just follow your normal build path.

Hextech Protobelt01 offers a great active that Karthus can definitely utilize very well in teamfights. Unfortunately it doesn't have amazing stats and it doesn't seem to fit into Karthus' build as it delays his powerspikes too much. I haven't really tested this item all that much on Karthus and when I get a better hang of it I will update this guide.

As I wrote in the pros and cons section Karthus requires a bit of a different approach to maximize his effectiveness due to Death Defied and Requiem.
In this section I'll describe my way of playing the champ at all stages of the game.

MID vs TOP lane Karthus

In ranked Queue I usually take mid as my primary lane and top as my secondary. Even though mid lane is preferable Karthus can still do just fine on the top lane due to the long range on Lay Waste that you can use to farm and also due to Requiem that is a global ability anyway. I occasionally experience some level of flaming even in champ select from my team if I take him top as teammates generally aren't used to seeing Karthus top. If you experience this then I would just advise you to ignore your teammates and do your thing.

EARLY GAME/LANING PHASE

At level 1 Karthus is actually surprisingly strong due to the fact that Lay Waste only has a 1 second CD. I like to use my Q to harass as much as I can at lvl 1. This means I have to use my auto attack for lasthitting the 1st wave. Whenever you see the enemy going for a last hit on the minion just use your Q on him. By the time you hit lvl 2 he should be low on HP already and should ideally be forced to use 1 or 2 pots straight away. After that be careful for when your enemy hits lvl 2. You don't want to be surprised by a Lux's Q or Annie's Q W Auto combo. At lvl 2 and beyond your playstyle should depend on what champion your playing against. Playing vs Fizz? Q him every time he goes for a cs and don't let him combo you. You playing vs Ziggs? Don't stand near your minions so he can't Q you easily and go for your own harass when he uses Q + Empowered auto on your caster creeps. Facing Kayle? Just sit back and try to match her clear if you can. Also remember with Karthus you can turn any lane into a farming lane. Your Q allows you to farm from a very long distance and your opponents should have a hard time actually dealing damage to you if you just sit back. One thing I have to mention here is Karthus' auto attack. It has a horrible animation and it deals little damage and you might be tempted to just use Q for farming creeps forever. Well I personally still recommend learning to last hit with your autos as it actually restores your mana if you manage to last hit a creep. It also allows you to use your Qs more frequently to harass the enemy laner.

I would suggest not to push your lane too much in the early game as you have no escape and low mobility and are therefore a sitting duck for the enemy if you pushed too far. This is especially true if you're playing Karthus top lane. I personally prefer to just freeze my lane near my tower if I can. You can freeze easily by letting your opponent clear your minions while you clear only on the enemy's melee minions. After that you let their caster minions push a bit and then you should stop them right before the turret range (so they are on your side of the map but out of the turret range). I only really push the lane if the enemy laner has gone back to the base or if he went for a gank on some other lane. I would also advise you to learn how to farm under the turret. it takes 2 turret shots and 1 Q to kill a melee minion and 1 turret shot and 1 Q to kill a caster minion. This will however require you to be very precise with landing your Qs so you only hit the minion that is under the attack from the turret.

I generally don't like going for ganks all that much with Karthus as he is very immobile and only really has his Wall of Pain to slow the retreating enemies down. With that said you can still make successful ganks even with Karthus. First you should hard push your lane (just clear the wave as quickly as possible, maybe even using Defile to do it). Then just go towards the lane you're about to gank and place a Control Ward in the river/red buff bush along the wave. If the path is warded i generally just clear the ward and return to my lane as the enemies probably saw you anyway if they are at least half competent. If the path is not warded however i just continue walking towards the lane I'm about to gank and try to place Wall of Pain on top of the enemy I'm trying to kill.

In S7 I think clearing wraiths or birds (or whatever they're called nowadays) is not worth it anymore as it takes longer to clear and takes too much of your HP to tank. Taking wolves if your lanes is pushed, however can be worthwhile as long as your jungler doesn't mind.

Keep in mind that junglers usually start blue buff and then continue their clear towards the red buff. At the 3 min mark you can anticipate a gank from the jungler (usually from their red buff side) so be careful as Karthus is very immobile.

Remember to always buy Control Ward on your 1st or at least 2nd back. For example if you're planning on going back to buy Catalyst of Aeons then don't back at 1100 gold but wait till you have at least 1225 so you can buy a Health Potion and a ward.
I usually use the control ward in the brush between blue buff and midlane. I also place the trinket ward by the enemy's wraiths. Alternatively I place the control ward in the brush between drake and the red buff and the trinket ward in the small brush in river.(Going to update this part of the guide with images at a later date) This generally gives me and my jungler complete vision of one side of the river so I can plan around the enemy jungler's movement.

At this point I have to dedicate a paragraph to Karthus' ultimate, Requiem. I've already written about the ability under the "Spells" section so be sure to read that first. Requiem is a global ability that does a substantial amount of damage to ALL of the enemy champions when used. To use the ult effectively you will have to know the enemy champions' health bars at all stages of the game. This means manually switching your camera to other lanes as often as you can. I was a masters Starcraft II player before I started playing League so I personally never had any problems keeping up with all the enemy champs but if you're just starting out Karthus you should try to just keep track of enemy champs as much as you can. Another thing to consider is the "passive" power of the ability (when the ability is not on cooldown). Requiem basically means that the enemy champs have 200 hp less then they actually have (with 1 point in Requiem). It means that they will have to recall not when they have 100 HP but when they have 300 HP or they get killed by you. Consequently it means that your other lanes will have a passive advantage over the enemies even if Requiem is never explicitly used. It is this passive power that really makes the ability so powerful early on.

MIDGAME

By midgame I mean the phase of the game after you get your 2nd item. You will get a huge power spike and will become a beast during teamfights. By now you should switch from just passively farming and waiting for kills with Requiem and try to actively taking down enemy turrets and taking dragons. You should try to force fights in areas where there is little room for the enemies to maneuver like in jungle or around the drake/baron pit. You should look to maximize your damage output by forcing your enemies to stand in your Defile range as long as you can. You can/should use Flash to aggressively enter the teamfight right after your team's main engage champ (with hard CC) goes in. You should use your Q to get the squishies down so they're either forced to stand near you and deal their damage (while getting killed by you) or they're forced to back away (and deal no damage).
Their frontine will be forced to either move forward out of your E and Q range or suffer serious damage aswell. If you use Karthus correctly you should be able to pretty much split their front and blackline apart while dealing massive damage to everyone. This will allow your team to only focus on the enemy frontline, thus essentially creating a 3v5 scenario.

There are a couple of champs that synergize really well with Karthus. Generally they are champs who can hit multiple members of the enemy team with hard CC like Amumu or Hecarim.

LATEGAME

By lategame I mostly mean a phase of the game after I get Rabadon's Deathcap. At that point the tier 1 and 2 turrets are generally destroyed and the fights are focused around inhibitor turrets, drake and baron. This phase of the game is very similar to the midgame for Karthus. You should generally still try to force teamfights in tight places where enemies can't maneuver that well. A good fight around baron where you position yourself properly can pretty much win you the game outright.

By this time the enemies will generally get items like Zhonya's Hourglass or Banshee's Veil to counter your ult. You should generally keep track of these items and their cooldowns so the enemies don't mitigate your damage outright. I advise you to use Requiem after you die in teamfights as by that time most of the ways of avoiding your ult will already be used.

24/11/2016: ITEMS: Added description for Abyssal Mask & moved it from situational to 3rd item.
Added description for Doran's Ring.
MASTERIES: Fixed Feast mastery icon.