Everyone seems to know about PVP, Questionable Content, and Penny Arcade, but what is that one webcomic that you love that it seems no one has heard of?
Dominic Deegan is my personal fav... he has a lot of fans out there and has been going for a good 10 years, but I didn't discover him until recently (met him at Nekocon 08). I don't know how big he's considered, but if you haven't read it yet, you should.
For one I know isn't as big, check out Between Failures. My guilty little pleasure...
I like Dawn Of Time ... it's nicely drawn and funny as well. The main character is Dawn, a cavegirl who rarely speaks (in fact, the majority of the pages have no spoken dialog). She has a pet dinosaur, and runs into the occasional time-travelling scientist or other anachronistic oddity.
I've been following a new comic just for the past few days called Parallax City. Not sure how it will pan out, but it looks promising. I really like the art style.
Demon Eater - It really is an odd one with an unusual subject matter and odd art style yet it all works. I literally follows a demon named Saturno from even before birth and it is both disturbing and sometimes oddly cute.