Wow... I guess I'll be the first one to say it but... "To hell with all the people who disable JavaScript." If your site requires JavaScript to run, forget all those people that have it turned off. Seriously. If your site really is good enough to worry about losing a substantial audience, it's probably good enough for people to turn on their JavaScript.
Case in point, go to Facebook, YouTube, Google Docs, Google Maps, or Digg (heck, try to do some of the more cool stuff with SO) with JS turned off and see what you can do (not a whole lot).
The web browser is turning into more of a cloud-based operating system than a portal to "web sites". There are just so many compelling reasons to allow JavaScript to run and, IMO, so few reasons not to. To me, turning off JS is akin to, like, enabling UAC in Windows Vista. Yeah... it's there to help prevent you from making mistakes but having it on is sooooo annoying (but the reverse logic... :-).
So, anyways... I might get a lot of flack for this answer but I feel that my reasons are sound and backed up by a lot of incredibly successful web sites and web applications.
Just make sure that pages you want indexed by Google (and most other spiders) are able to be accessed without JavaScript on.