I prefer Pylons. I've built all sorts of things with it:

* A RSS-rewriting, caching "proxy" for the News.YC feed

* A search engine for 2 gigs of email, going back to 1995

* A customized CMS-like app

* And now, my blog, which I'm almost done writing; I keep making changes to the architecture.

TurboGears 2, which some have recommended, is being built on top of Pylons.