The Emperor is actively watching over and guiding and protecting mankind. He is definitively 'alive' (well his mind is). This goes hand in hand with the new Heresy fluff, with the Emperor keeping daemons from spilling onto Terra through the disrupted webway. It also suggests he acts against the influence of the Chaos Gods and fights against warp entities and closes warp rifts.
The third ed fluff of humanity evolving to become a more psychic race is back. Additionally the book states if mankind can weather these evolutionary changes and master its psychic gifts then a new golden age beckons. So there's some hope beyond the 'time of ending' now.
Mankind is one of the few races able to use the warp, most can not. Most of those which can do so less reliably than man.
There's clarification on the different types of Exterminatus. Cyclonic torpedoes, atmospheric incinerators, devices deployed on the surface of a world, sustained planetary bombardment.
Chaos is once again the prime threat. Chaos Space Marines and renegades, rebellious worlds, secret cults, daemonic invasions, warp rifts and storms and the whispered temptation of the dark gods.
Squats are back as a recognized and permitted ab-human strain. There are 73 stable abhuman strains recognized.