I was playing around with the 960 Grid System earlier today and found it to be a compelling framework for web development. You will need to have at least a novice to intermediate understanding of CSS to utilize the 960gs. The video below is a nice overview of the framework and runs about 25 minutes.
For more information check out tutsplus and if your a drupal fanatic like me be sure to grab the 960 grid system for Drupal. It offers a great alternative way to go from photoshop mockup to tangible drupal layout.