Stuff You Should Know - Hosted by Josh Clark and Chuck BryantEclectic, quirky, nerdy, and quite informative. They cover everything from minor historical characters to things like "how lying works." It's basically a grab bag of informative, mildly humorous goodness.
TED Radio Hour - From National Public RadioIt's not really fair to other podcasts that this one always features geniuses, but so it is. If you like having your mind stretched, mashed, and then filled with entrepreneurial an creative ideas this one is for you.
Gleeman and the Geek - Hosted by Aaron Gleeman and John BonnesThese two avid, experienced and intelligent Twins bloggers now host a radio show/podcast. Equal part sabermetric argumentation, fan boy rants, and reasoned rational about my beloved Twins this podcast is a favorite. The team may stink, but its bloggers are the best.
Here's the Thing - Hosted by Alec BaldwinYes, that Alec Baldwin, the same one who plays Jack Donaghy. Except now he's the pointed, smarmy, insightful, charismatic and eminently likable interviewer of all sorts of celebrities. Oh wait that sounds a lot like Jack Donaghy. Except for the insightful part.
This American Life - Hosted by Ira Glass
I feel a little like this is cheating, but whatever. It's my blog. This show is simply the best in real-life story telling with great variety. Contributors include humorists, short story writers, amateur journalists, professional interviewers, investigative journalists, and even a few fabricators of fact (here's looking at you, Mike Daisey).