I've tried out a lot of podcasts in the past year or so, and a lot of them are decidedly mediocre. These are the ones that have proven they're worth keeping in iTunes.
Diggnation is hosted by Digg founder Kevin Rose and Alex Albrecht, and covers some of the most popular stories from Digg. The two of them sit on a couch with their laptops and drink beer while discussing news stories. You definitely want to get the video version of this one. Posted weekly.
The Totally Rad Show is just that: rad. It's hosted by Alex Albrecht (of Diggnation) along with Dan Trachtenberg and Jeff Cannata. It's sort of a geek tour de force: they discuss movies, TV shows, comic books, and video games. It can be a little cheesy, but they're reviews and arguments are as entertaining as they are informative. Posted weekly.
A video version of The Onion.
Daily radio news from The Onion - short and sweet.
Hosted by Ira Glass, This American Life tells a variety of stories on Chicago's PRI. The radio show is posted weekly after airing on the radio.
The weekly out-loud call-in version of Dan Savage's sex advice column. Dan's a funny guy to listen to, and it can be informative. I wouldn't listen to this one at work.
A weekly roundup of Mac news, hosted by This Week In Tech's Leo Laporte, Merlin Mann, Andy Ihnatko, and a rotating band of commentators. It's probably only about 50% Mac news and a lot funnier than you'd expect.
I wish this one was updated more often, because it's probably my favorite. God is a regular guy, the Devil is his ex-girlfriend, and Jesse (Jesus) keeps pushing for an insurance plan that covers crucifixion.
Abigail is a 13 year-old girl with Bloomberger syndrome, so she looks like a 35 year-old man, but she still hangs out with her BFF Madison and has a thing for her classmate Lance. Hilarious every time.
The Midwest Teen Sex Show offers sex advice to teens. I can't explain how funny this actually is, so I won't bother trying.