- You'll be doing a lot of JS. Just use jQuery. It's the most popular of the JS / AJAX frameworks, so even if you decide not to use it later on, it's a good starting point.
- I dig Ruby / Sinatra. Never really got into Rails or Django. You can learn how to use Sinatra + Haml + Sass in a few minutes. I've also learned that, somewhat to my surprise given my previous perception of their fan-bases that I don't really like Python and much prefer Ruby.
- For novelty there's Wt (http://www.webtoolkit.eu/wt), haven't brought myself to actually use it for anything though.
- CSS grid layout "frameworks" make things easier. I used (http://code.google.com/p/blueprintcss/) for our new site, but can't say that I had much love for it -- though still much better than doing all of the layout by hand.