I definitely second Stuff You Should Know and This American Life. (You can listen to past episodes of This American Life from the archive on the website for free).
Quirks and Quarks from CBC Radio is among my favourites (and will be starting again after a summer hiatus). It is a very interesting and accessible science-related podcast. CBC Radio has a few other podcast that I selectively download from, too (The Current, Q:The Podcast).
o, and NPR has some great podcasts, too. I do not have any right now on my list, but for a long time, I was really into All Things Considered, and a few of the specific topic-related podcasts (Environment Food, etc.).
Savage Love with Dan Savage is also great.