Girl Genius, winner of several awards for both story and art, a story about a world ruled by MAD SCIENCE: http://www.girlgeniusonline.com/
8-bit theater (finished now), an overall parody of Final Fantasy: http://www.nuklearpower.com/2001/03/02/episode-001-were-goin...
Megatokyo - it used to be pretty big among manga fans, I don't know if it still is: http://megatokyo.com/
Savage chickens, a strip drawn in sticky notes: http://www.savagechickens.com/
Basic Instructions - hard to explain, but still, very funny: http://basicinstructions.net/
Penny Arcade, one of the first "big" webcomics, from the same guys that run PAX: http://penny-arcade.com/
Manly guys doing manly things, an overall parody of macho characters in popular culture: http://thepunchlineismachismo.com/
XKCD, terrible (minimalist?) drawing, truly great writing (if you are geek and/or math inclined): http://xkcd.com
Keep in mind that for new readers it is usually better to start from the first strip and move on, but that usually means that you have to endure some pretty terrible artwork (check the "first" button, and move on).
Also, it depends a lot on what you like reading - XKCD is almost exclusively math-oriented while Penny Arcade is not really funny if you are not into videogames. Then again, that's the good side - there's something out there for everyone.
• The not-updated-often-but-still-great « perry bible fellowship » : http://www.pbfcomics.com
• The overly optimistic « Buni » : http://www.bunicomic.com/
• The Norwegian POV : http://www.optipess.com/ (relevant to main topic http://www.optipess.com/2010/09/20/no-girls-allowed/ ; or to news http://www.optipess.com/2010/10/08/missing-piece/ )
• Not always SFW (depends where you work of course) :
• Science, Sex and Fun « Saturday morning breakfast cereal » : http://www.smbc-comics.com
• Often trashy but also often very funny « Cyanide & Happiness » : http://explosm.net/comics/Sinfest: http://sinfest.net
Why you should check it out: Great illustrations. Mid-to-Long story arcs, with single shorts thrown in full color panels on Sundays. And it is SFW.
Questionable Content: http://questionablecontent.net
Some find it a bit insipid and too self-referential at times, but it has it's brilliant moments. Also (mostly) SFW.
Piled Higher and Deeper - grad students. http://phdcomics.com/comics/archive.php?comicid=591
Extra Ordinary - surreal humor. http://www.exocomics.com/05
Boy on a Stick and Slither - surreal humor. It's dead now, and judging by my friends is a minority taste, but has several of my favorite strips to its name. http://archive.boasas.com/?c=286
minus - more surreal humor. Also dead, but excellent. http://www.kiwisbybeat.com/minus13.html
Jesus and Mo - making fun of religion and the stupid things it inspires people to say. http://www.jesusandmo.net/2006/05/11/skin/
Sam and Fuzzy - Hard to describe. The cartoonist does a great job making sure there's a joke in every strip, despite involved continuity. http://www.samandfuzzy.com/1482
Station V3 - originally great. Hit such an awful dry spell that I unsubscribed, but hey, maybe it's funny again. http://www.stationv3.com/d/20110722.html
Of those already listed, I also endorse savage chickens, xkcd, basic instructions, and sinfest.
http://www.savagechickens.com/2010/11/identification.html
http://basicinstructions.net/basic-instructions/2010/1/10/ho...
I rather like these two: http://www.achewood.com/index.php?date=12282007 http://www.achewood.com/index.php?date=01272003
http://telegraph.newsprints.co.uk/view/14935264/tg3482987_ma...