Rat’s. I agree it deserves the second mention though. Randy has also managed to have the characters age and mature in a realisitc fashion as the series has progressed while keeping it just as funny as it ever was.
It’s one of the few web comics that I would buy in book form, and one of the few that doesn’t have a book out.
I like Dr. McNinja enough that I bought the shirt. I also had it get recognized in 7-11. Woo hoo!
Stop what you’re doing and read The Perry Bible Fellowship. You owe it to yourself. Really, you do.
Another vote for Schlock Mercenary. And it’s daily and the author has never missed a day.
For something more surreal, try Stickman and Cube.
In fact, tvtropes has a whole page on Dada Comics.
You must read it. There’s not a lot of material, but it’s so… indescribably beautiful, surreal, sad, funny, peculiar, bizarre, and comforting all at the same time. It feels very much like a spiritual relation of Calvin and Hobbes. If you enjoyed C&H (and really, who hasn’t?) you’ll love Copper.
Another favorite of mine is Gone with the Blastwave, about a seemingly pointless war in the post-apocalyptic ruins of some vast city. Beautiful art and lots of dark humor.
One more somewhat obscure recommendation is Fleep, a short series of strips about a guy who wakes up to find himself mysteriously trapped in a phone booth encased in concrete, and with only uncertain memories of how he got there. He has to use the limited resources at his command to figure out a way to escape.
Scandal Sheet! by former doper Chef Troy
Truck Bearing Kibble which is keeping my need for Perry Bible Fellowship at bay
Friendly Hostility the heir to Boy Meets Boy
Sinfest which is delightfully insane
Two Lumps which is required reading for any cat owner
The Comics Curmudgeon for all your comic-mocking needs
Can anyone dig up the previous thread on this? I know there were some in there I’ve been meaning to get back to, and the 300 second search is really getting annoying. Note: don’t search “webcomic” in titles only.
In the meantime, I’ve recommended this one before, but Ghastly’s Ghastly Comic is highly amusing. The tagline is “Tentacle monsters and the women who love them.” I didn’t think tentacle rape lent itself to all that much humor, but it’s really well done. Linked comic is SFW, but clicking through the archives will uncover scenes of tentacle sex and or penii.
Ha; yes that’s a good one.
Some others that haven’t (I think) been mentioned:
UserFriendly: http://www.userfriendly.org/ Geeky, technology-based humour.
What the Duck: http://www.whattheduck.net/ Based around photography.
PhD: http://www.phdcomics.com/ Hilarious strip about graduate school and academia.
I want to put in a plug for Real Life Comic .
Start at the beginning. Has geeky overtones, but is quite good. And, he’s from my old hometown! Yay!
I’m not sure if it’s technically a comic, but I’m very fond of A Softer World – it’s often poetic, sometimes darkly funny, gut-wrenchingly melancholic and I really can’t recommend reading through the whole archive in one afternoon if you’ve got booze and sharp objects in the house. (Though if you absolutely must read through the whole archive in one afternoon, having at least booze at hand is recommended, and at some point, sharp objects just ain’t so bad any more, too.)
Misty the Mouse hasn’t been updaded in about a year and a half, and was completely offline for months, but is a good read.
Kevin and Kell isn’t strictly online anymore (at least one newspaper has started carrying the strip).
AFAIK, Pibgorn is still online only, and I’m surprised nobody’s mentioned it.
A Doemain of Our Own is winding down but the archives are online. A couple dates in there, such as 7/20/05, aren’t exactly work safe.
I just got done catching up on the archives for this one. Once the story gets rolling, it really is very good. Bonus: He draws women well. Yow.
I’ve recently been enjoying Nodwick , Full Frontal Nerdity, and particularly PS238. All three are apparently written by the same guy(s).
Nodwick and Full Frontal Nerdity are both comedic D&D/roleplaying comics, the former being about an NPC and his hellish mistreatment at the hands of his party, the middle being a “RPG buddies get together and say stuff” piece, and the latter essentially looking like the K-6 version of **Magellan **, insofar as it’s about an elementary school for the (superpowered) children of superheroes.
Crimson Dark is a great scifi comic about privateers.
I used to hate Misfile, but it’s grown on me as the writing has gotten better.
Oh, and Arrogance in Simplicity definitely deserves a look.
Another mention here for The Adventures of Dr. McNinja (Now In Glorious Extra Colour! ;)), which is brilliantly absurd and never fails to make me smile. I’m seriously tempted to get a shirt, but I just can’t decide which one! 
I’m also going to mention those webcomic staples Penny Arcade and Ctrl+Alt+Delete.
They’re both gaming orientated, and Penny Arcade is (IMHO) the consistently funnier of the two (Ctrl+Alt+Del has recently taken a turn for Teh Serious, which isn’t really what I’m after in a webcomic, but YRMV).
You don’t have to be a gamer to fully appreciate either of them, but it does help with some of the references…
I forgot to mention Medium Large by Ces Marculiano who is the writer of Sally Forth. ML is much better.