It's a pretty heavy overhaul. You'll want to spend some quality time with the book before trying to play a game, it'd be an awful lot to be introduced to as you go if you're an experienced 4E player.
The most controversial change is of course true line of sight. There is no more nonsense about size classes and area terrain. *ALL* shooting is now bend down over the table and see if the model can actually see the target.
Casualty removal has been heavily overhauled. Wounds are assigned round robin now, you can't protect sarts/special weapons to the very end. e.g., 10 marines with a flamer, ML and sart take ten wounds. Each special model, Flamer ML and sart, must each take an individual saving throw. Also applies in assault.
Assault has been made even more rapid and brutal than 4E. All units now have counter attack. The LD modifier when you lose is the difference in wounds inflicted. No Retreat! Is now based on wound differential rather than outnumbering. That will be brutal against big ork mobs and big gaunt broods.
Vehicles in general are much harder to kill, except of course skimmers received the anticipated nerfing.
Pretty much every single section of the 4E book has received at least one tweak that fundamentally changes the way a rule works. Read up!