Starting a mid-size site (about 25 templates). Thinking about a grid framework this time instead of hand-rolling the layout. 960.gs or Blueprint 0.7? Or YUI Grids?
Main concern is handing it over to the client's in-house guy later.
960.gs. It's smaller, it doesn't touch your typography, and the 12 and 16 column versions cover most designs. Blueprint resets and styles a lot of things, which you then fight with.
The thing nobody mentions: class="grid_4 alpha" all over the markup is presentational. Fine for a site you maintain. For the client's in-house guy it's a convention he has to learn.
The 960 PSD and Fireworks templates also help. Give the designer the template, then the grid in the PSD matches the CSS. That alone saved us a day of back and forth on the last project.