I doubt there's anything close to enough $ in NASA's budget to develop a 500,000 lb lift vehicle. If NASA's budget was to get a huge infusion of $, I'd like to see:
1) Manned Mars mission
2) More aggressive robotic exploraion of the Jovian system, focusing on Europa (and either Callisto or Ganymede, whichever of those two is icy and potentially hides an ocean). Follow up with manned missions once technology allows this.
3) Observatory on the Moon, with a very large telescope and other instruments for the various EM wavelengths, though with adaptive optics, maybe it isn't necessary to put instruments beyond Earth's atmosphere any longer, at least for certain wavelengths.
4) More aggressive development of terrestrial planet finding missions/technology.

Given NASA's limitations, I'll stick with #2 and add Mars to that as well as #4. I guess I just highjacked this thread, apologies...