There may be spoilers below so if you aren't up to date with Supernatural, it is recommend (by me!) that you catch up with current episodes. You have been warned! And you can also check out the season trailer...
Since the season is based on God's sister the Darkness, or Amara as she's known by to the brothers. No matter what the brothers do she has God level powers. When she was released by Dean having his curse mark removed from season 10. And as anyone who has been locked away by God since probably the beginning of time, or eons at the very least, Amara is out for revenge.
The biggest problem is her power. In my opinion, it seems very overpowering to put God's sister in the show if there isn't even anything strong enough to defeat her. All the angels in heaven attempted to smite her but failed. Even Lucifer attempted to use a Hand of God against her, which also failed. For this reason God must definitely appear in any way- even just a real dream to Sam not sent by Lucifer. TVline stated in one of their articles that Rob Benedict will appear again as Chuck, God's latest prophet.
The brothers therefore need Lucifer to be freed. Of course Lucifer, being the Devil and all, end up taking over Castiel and overthrowing Crowley as the king of hell, and deciding to annihilate the human race, as he does. So then they had to deal with both Amara and Lucifer. With an angry Crowley with them they have to take care of Lucifer before the Darkness but Amara ends up kidnapping Lucifer.
To further her ends Amara threatens to kill Lucifer, the first and probably favourite son of God. But will God show himself for the Devil? But maybe he's already helped out the Winchesters. In episode 17, 'Red Meat', Sam nearly dies or does he actually die and is there a greater power in action behind it all? TVline also stated that God would be focused upon more in the second half of the season as well as the effects of Death's death (that just sound weird but yeah!)