Dean: Sam, I got a bad feeling about this.
Sam: Well, you'd be nuts to have a good feeling about it.Dean: You know what I mean. Detroit. He always said he'd jump your bones in Detroit. Here we are.
In a reality constructed by Zachariah to try and convince Dean to become Michael's vessel, Future!Dean tells Dean that Sam went to Detroit alone, gave Lucifer permission to possess him, and the Apocalypse proceeded with the spread of the Croatoan Virus and the deaths of millions.
After Dean and Sam fail in their attempt to kill Lucifer with the Colt, Lucifer asks Sam whether he will agree to be his vessel. When Sam refuses, he informs Sam that he will say yes to him soon "within six months. And I think it'll happen in Detroit."
Later, when Sam, Dean, Bobby, and Castiel go looking for Lucifer with the plan to use the Horsemen's Rings, Dean recognizes that a sudden temperature drop in Detroit is probably a sign that Lucifer is there. Sam agrees to become Lucifer's vessel as a part of a plan to carry Lucifer back into the Cage. When Sam is unable to regain control, Lucifer leaves Dean, and Nick's discarded body, in Detroit as he prepares for his showdown with Michael.
In Castiel's attempts to reach the Men of Letters Bunker after becoming human, he is forced on a detour due to angels pursuing him over his perceived involvement in their fall from Heaven, ultimately ending up in Detroit. While foraging through the trash for food, Castiel meets April Kelly, who offers him shelter during a rainstorm.
Arriving at April's apartment, she proceeds to tend to Castiel's arm wound, culminating in the two kissing and having sex. The next morning, April reveals herself to be a reaper, telling Castiel she had possessed and killed the real April. She goes on to restrain Castiel and torture him for information on Metatron and the fall. When Sam and Dean arrive, due to Gadreel locating them, Castiel is fatally stabbed and a small skirmish ensues, culminating in Dean killing April and Gadreel taking control of Sam to resurrect and heal Castiel.