When I built this site I decided to break semantics and use a 960 grid.
For about the last year I've been hearing about the power of using a grid to do site layout. At first I was hesitant to take a look at them because they break site semantics. Semantics are important and they are something I've preached for some time. I thought of grids as a great tool for rapid prototyping but, not as a tool for production sites.
Why You Should Consider A Grid
You could listen to me ramble on about why grids are good to use or you could listen to Nathan Smith and Todd Nienkerk talk about why they are good, how they work, and a Drupal base theme built around the Grid. These guys know this stuff better than me and there's video with slides so, watch the video to learn about the magic of grids.
If you decide to try out using grids here are a few resources that should prove useful: