As far as being known from Youtube is concerned, I'd say Egoraptor and Game Grumps, TotalBiscuit, and TomSka.
As far as being hosted on Youtube as well is concerned, I'd say JonTron, Retsupurae, Chip & Ironicus, and Continue?.
As for why:
Egoraptor - Does really fun and surreal animations that are packed full of quick, short jokes. Also does the more serious "Sequelitis", which is fairly informative and an interesting examination of things that sequels do well or stumble over compared to their predecessors.
JonTron - Does extremely silly, over-the-top reviews of silly, over-the-top (or bad) media.
Game Grumps - Egoraptor and JonTron play games, make jokes, and talk about game philosophy. While they often say things I might disagree with, it's still generally interesting to hear their points of view and take into account their side of the discussion.
TotalBiscuit - I typically only watch his "WTF Is..." series, because he's rather informative about games I otherwise wouldn't have known anything about, and he can be quite funny and self-deprecating at times (such as any time he needs to play a puzzle-platformer).
TomSka - The guy is full of random, front-loaded humor and is a great voice actor. His sketches usually have rather high production values too, for being a Youtube channel.
Continue? - They're from Normalboots.com, the same place JonTron is hosted. It's three guys making jokes while playing older games and basically seeing whether they hold up today or not after playing the first half hour or so, and then giving a verdict on whether they would 'continue' to play the game or not.
Retsupurae - They do a few different things, with a similar motif: They riff over media.
They have longplays, generally of mediocre or bad adventure games, that they riff over which I don't find as consistently amusing because there's no terrible commentary for them to rip apart. They have flash animations, which they take from Newgrounds.com, play through and then riff over - Which is a lot more amusing because the "games" last for a much shorter period of time and there's the truly ridiculously low-quality things for them to tear apart, not to mention the plethora of "10/10" reviews and comments on Newgrounds that they mock afterward.
And then they've got bad Let's Plays from Youtube, where they take the creme de la creme of poor quality videos - Camcorder LPs, Unregistered Hypercam LPs, LPs with little or awful commentary, LPs where the player just sucks at the game, etc. - and absolutely demolish them. This is when they're at their best, in my opinion, because they can play off of the poor recording, the bad commentary, the bad playing, technical difficulties, or any number of other things.
Chip & Ironicus - Chip Cheezum does a bunch of Let's Plays for SomethingAwful, hosted on blip.tv, and Ironicus is his primary co-commentator. Aside from their first two games they ever did, they've got really good quality on their videos and their commentary is top-notch. I've watched their 50 Cent: Blood on the Sand LP probably three times through. They also retsupurae bad Youtube videos, both on Chip's own channel and occasionally guesting in Retsupurae videos.