The amount of people that seem to be missing the point of Fallout being that its a post-post-apocalyptic world, focusing on the rebuild of civilization, not the immediate aftermath of the collapse of it, is more then a little disheartening... Seriously, we have enough media franchises that focus on scavengers, raiders and mutants fighting over the last precious cans of beans, dog food, and bottled water in a grimdark fatalist setting without Fallout shifting to focus on that as well. A little of that is good, but it isn't, and shouldn't be the focus of the franchise.
OT:
1. Replace the Pip-Boy 3000 with (or provide the option to use) a hand-held variant, preferably based on the Pip-Boy 3500 mod. I know that there are lots of people that like the 3000, but based on the existence of the 3500 mod there are people like myself that don't like having a clunky hunk of metal mounted on our arms that ruins the look of several armour sets, and even outright breaks any sense of immersion one can have by causing the player character to have exposed flesh when wearing a radiation or space suit. Anyone with even a rudimentary understanding of how space or radiation (even Fallout's 1950's SCIENCE! radiation) works understands why that would be a very, very bad thing.
2. This is a given, but a new area to explore, if on the east coast the Commonwealth (or at least part of it) for damn sure. After the way Bethesda built it up they have to let us explore it.
Otherwise, maybe the middle of the country, seeing as how the west coast has been pretty well explored by now, and is on top of that has been mostly settled by the NCR, leaving little untamed frontier to explore (knowing how Fallout tends towards the more optimistic endings as canon the Legion being in ruins, if not gone outright is practically a given, so there would be no worries there).
3. Brand new enemies. I know that Super Mutants are a series staple, but they were shoe-horned in when it came to Fallout 3, if you must include them do so sparingly! You guys have more then enough creative muscles to compensate, so flex those muscles dammit!
4. A more in-depth combat system, for melee and ranged both. Melee weapons that are as deep as Skyrim's (swords having increased critical chance, blunt weapons ignoring a portion of an enemy's DT [or DR]), etc. Ranged weapons that handle (please note the emphasis on HANDLE) like one would expect in a proper shooter eg. NOT SHIT, yet balanced to make melee weapons a real option, maybe by making cartridges somewhat expensive and rare (explosives even more so) if they go for the frontier setting again.
5. Tread new territory! We've seen enough of the Brotherhood of Steel, enough of the Enclave, enough of the Super Mutants, enough of the New California Republic, enough! Introduce us to new wasteland factions, allow us to experience new stories! The Vaults are an integral part of the Fallout mythos, and New Vegas handled them well. There's no need to cut them but again, use them sparingly! Flex your creative muscles Bethesda/Obsidian, we all know you can do so and do so beautifully!