1. The same engine that Fallout 3 used (possibly confirmed) with some improvements
2. The game taking place in the same 'world' that Fallout 3 did
3. More perks
4. More weapons, armor, other items
5. New kinds of drugs, medical items, and the like
6. More non-combat options, like more houses, more house items, and interesting non-combat options (Ex: Like selling random people into slavery in Fallout 3)
7. The option to possibly begin the game as a race other than human (Maybe ghoul, or Meta Human super mutant? Maybe this could be an option you'd unlock after beating the game the first time?)
8. More areas
9. More interesting places like Tranquility Lane, the Alien Crash Site, the Dunwich Building...
10. More achievements, and more downloadable content
11. More balanced followers
Essentially? More of everything, while retaining the basic 'identity' of Fallout 3.