A non-US setting would be nice, with more of a focus on a large ruined cityscape. Walking around the city in Fallout 3 was one of my favorite things to do in the game. Fallout: Venice might be pretty nifty.
Keep weapon mods, add Pip-Boy mods. I don't want my Pip-Boy to just be a computer, flashlight, and radio. Fuck that, I want to be able to turn this thing into Glitch from Reboot. "Pip-Boy, taser! Pip-Boy, zipline! Pip-Boy, reclining armchair!"
Actually, while I'm thinking about mods, the option to replace your limbs with stuff! Get your legs blown off in that last scrap with the Super Mutants? No problem, crawl your miserable hide over to the nearest city, find an engineer and have him give you those nifty thrusters from some of the robots instead! You don't use that left hand much anyway, may as well have that replaced with a mechanical riot shield/laser rifle combo! New Vegas didn't go far enough with that, there must be more!
The option to become a ghoul would be nice. Maybe a chance of occurring if you spend too much time with a really high radiation level? Bonus: healing from radiation, small STR boost maybe? Negatives: Massive CHA penalty and just about everyone requiring more work to get to like you.
Maybe with a high enough science skill and the right perks, the ability to capture and tame some of the wasteland critters? Rad-scorpion ranch anyone?