I liked the isolated, "one man vs the Wasteland" feel of Fallout 3 better than the that of New Vegas, so I hope that it is set in another location that has been subject to massive nuclear damage.
Other than that:
1. New art assets
2. New character animations
3. Keep the great support for mods
Other than that:
1. New art assets
2. New character animations
3. Keep the great support for mods