1. Cars can be repaired/upgraded.
2. The dating aspect of the game is gone. You still have a cell phone, but only people you meet in the game will call you to ask you to do a mission or something else before the mission.
3. Weapons include the usual arsenal you'd expect, but flamethrowers, laser trip mines, and remote control mines are included. It's possible now to pick up objects in a buidling/street to use as a weapon. There's also a museum where it's possible to steal axes, swords, etc.
4. It's possible to rupture a fuel line, and if you shoot at the trail of gasoline, it will lead straight back to the car, blowing it up.
5. Mini games such as bowling, darts, ect. are all gone. You can enter triatholons, gamble, play basketball, and more.
6. Character customization is back, but only in terms of clothing, weight, etc. The character you start off with can't be altered by age, height, race, etc.
7. No children at all.
8. There's now the ability to grab people and use as shields in hostage situations.
9. The cops are much more realistic. If you kill somebody when there are no cops around, you won't run the risk of one star as often as you would in GTA 4. The cops will use dogs and rams to knock down the doors of buildings you're hiding in.
10. You can enter some buildings and lock the door or push objects in the way to barricade it.
11. You become better at things as the game progresses. If you only ride motorbikes then you'll increase your skills, same as weapons.
12. Weapons can be customized and some even home-made.
13. One mission involves breaking out a familiar GTA icon from a previous game.
14. Rain and even tremors will appear in the game.