Penny Arcade [http://www.penny-arcade.com/comic] should go without saying.
XKCD [http://xkcd.com/] is one of the best webcomics out there, probably because it proves you can have intelligent humor using stick figures, and probably because Randall Munroe is such a geek that we can all relate to what he says.
Awkward Zombie [http://awkwardzombie.com/]'s always been a great one for lighthearted gaming wit.
Recently, I stumbled across Cucumber Quest [http://cucumber.gigidigi.com/]'s TvTropes page, and thought it looked cute enough to have a go. It's adorable and funny, taking a couple pointers from hiimdaisy's style of comedic lampshading and going from there.
I would recommend Darths and Droids [http://www.darthsanddroids.net/] to anyone who likes Star Wars and DnD humor.
Pinkamena said:
Homestuck, basically. Because it's like fucking crack.
I live and die by those updates more than any other work of media. I find it appeals to a certain part of your mind that little else can reach. Probably because Hussie can grab your hand and walk you deeper into the narrative, occasionally stopping to fling you off a three story drop and yelling "Enjoy the additional depth! Me and the context'll catch up with you in a bit!"
Since we're talking about Homestuck, I suppose there's a couple more I should mention. Nightfall [http://mspfanventures.com/?s=620]'s a good Homestuck-based fan adventure; the author's got a unique art style as opposed to the sprite manipulation of some of the others, some great character moments, and a solid understanding of the setting to work from. I'd recommend it to anyone who's current on Homestuck, itching for a bit more supplemental story, and who likes the character Vriska.
Prequel (or Making a Cat Cry: The Adventure) is an MSPA-styled adventure set in pre-Oblivion Cyrodiil. It's fantastic, adorable, and slightly sadistic with regards to its main character. It should be an excellent read to any fan of Oblivion.
That's all off the top of my head. If there are any more, I can't think of them.
I used to have at least dozen more in the past, but I don't follow them much (if at all) anymore. I guess they just stopped being good enough for my tastes.