Tighter on-foot controls, and more checkpoints
While some people didn't like the semi-realistic driving of GTA 4, we thought they struck a good balance between being demanding and rewarding - a slight shift towards a more arcade style handling model wouldn't be bad though. The out-of-car handling, on the other hand, could clearly do with tweaking.
In all fairness to the developers, Red Dead Redemption was a marked improvement when it came to the nuts and bolts of combat - especially in terms of the cover system. If Rockstar carries over what it has learned from last year's game, there shouldn't be too much to worry about. While we're on the subject, LA Noire employed a pleasingly economic setup for its on-foot chase sequences, borrowing a few touches from Assassin's Creed's free-running controls. A revamped variation of this could help GTA 5's antihero to be a bit more nimble than Niko Bellic, who occasionally struggled at gangster athletics.
With regards to checkpoints... well, what more is there to say? GTA 4 simply slipped up in this regard, dumping you way back at the start of a mission and robbing you of your guns and armour. This was a particularly annoying issue on longer excursions, like the bank robbery and getaway in Four Leaf Clover. Thankfully, this problem was more or less dealt with in the DLC expansions - The Lost and Damned, and The Ballad of Gay Tony - so hopefully we'll get them from the start next time.