Fallout 3 had some interesting weapons like the Experimental MIRV, alien atomizer, Mesmetron, gauss rifle, and the auto axe to name a few. The problem is a lot of weapons were variants of a type and not very distinct from one another. I might be using a unique Blackhawk revolver, but it looks the same as a normal .44 magnum revolver. Weapons should be more distinguished from one another.
Also, we are in a sci-fi universe, so why not more imaginative or zany weapons? The alien weaponry and plasma arms were cool, but surely we can do more? Take Red Faction: Guerilla and Armageddon for instance. In those titles we had Singularity Grenades, Nano Rifles, Napalm Lasers, and Mr. Toots for crying out loud! Granted, those games are set in the far future, but we could have something similar in the new Fallout games. Or even just alternate fire modes like the firearms in Bulletstorm. It would be great to see the developers go hog wild with some inspired designs that are fun to use.