In no particular order, these are my favorites:
Questionable Content- I don't think anything more needs to be said.
Girls With Slingshots- The artwork is adorable, the storyline is interesting, and I wish the characters were my friends. Because it's also a slice-of-life comic, it's a nice complement to QC when I'm catching up on my dailies.
Blip- This one's a little less well-known. The plot is seriously fantastic, and Sage Leaves does a good job of keeping the reader in suspense every day. The whole comic is built on the concept of the creation of a girl who was never supposed to exist- god made a mistake. Really interesting stuff.
Hark! a Vagrant- ANDREW JACKSON IS AS TOUGH AS OLD COCK.
Octopus Pie- Another essential webcomic, of course.
Wasted Talent- Wasted Talent is an autobiographical webcomic revolving around the lives of Angela (Jam the Engineer), Trevor (her husband), and her coworkers.
xkcd- Yeah, needs no introduction.
Hyperbole and a Half- This webcomic (blog?) is really something else. Allie Brosh has a quirky sense of humor, and it shows. Her illustrations are all done in the Mac equivalent of MS Paint, but they're all very well-done.
Anders Loves Maria- AKA Anders Has Sex With Anything That Breathes. Very NSFW, but the artwork and plot are compelling.
Something Positive- I don't keep up with this one much anymore. The combination of tiny text, clumsy navigation, and NSFW ads keep me away, but it's still considered an "essential."
Johnny Wander- Made up of a boyfriend/girlfriend team; largely autobiographical. Incredible artwork, cute, and funny.
Max VS Max- I discovered this one not too long ago. It deals with several Christian themes throughout, but it's charming enough to the point where nonbelievers would find it interesting anyways.