Two scientists are working at Niveus Pharmaceuticals, checking test animals as they prepare for a new vaccine. The janitor suddenly jabs a needle into one two of them, says he's running an experiment, and locks them in. He then destroys the lock and watches as the infected scientist goes berserk and attacks the other one, tearing him apart. Satisfied, the janitor leaves.
Dean and Sam pose as CDC agents and visit a hospital where people are turning up sick and need vaccine. They figure it's some version of the Croatoan virus and ask about signs of violence. However, the doctor in charge insists that it's simply swine flu. When she mentions that the first case turned up a day and a half ago, they realize it was the same time as statues started crying.
Back on the road, the brothers brief Bobby and wonder what Pestilence is up to. It's the fourth town that he's hit and they have no idea where the Horsemen will turn up next. They figure he's heading east and that's the best they can do. After Bobby hangs up, Crowley suddenly teleports into the back seat. When they skid over, Crowley teleports outside and tries to talk to them. Sam figures he set them up, knowing the Colt wouldn't work on Lucifer, but Crowley denies it. The Winchesters manage to calm down long enough for Crowley to offer them Pestilence. Dean considers it, much to Sam's surprise. Crowley insists he wants Lucifer dead, and now Lucifer knows he exists and burned down his house and ate his tailor. Now every demon is trying to kill him. Crowley asks them to come with him and admits he knows about the Horsemen rings. They finally agree and go to a nearby abandoned house.
Once they're secure, Crowley explains that he hid a magical coin on the Impala when they broke into the car, and he's heard everything they've discussed. He wants in on their plan to imprison Lucifer, and explains that he knows the demon that handles the Horsemen's travel plans. Once they capture him, Crowley plans to use his persuasive abilities to convince the demon to switch sides.
The demon, Brady, is a CEO at Niveus Pharmaceuticals. He tell his staff that they need to produce swine flu vaccine as quickly as possible. One of the staff, Mitchell, tries to protest. Afterward, Brady calls Mitchell in and tells him that he has the perfect position for him. He then cuts Mitchell's throat and uses the blood to contact Pestilence and tell him that they re moving ahead on their plans to distribute the vaccine.
As they pack, Sam wonders why they're listening to Crowley. Dean admits that it's insane. Crowley comes in and insists that Sam stay behind because he's too eager to kill him. Dean reluctantly agrees and leaves with Crowley. Sam calls Bobby to tell him what happened. He then asks how Bobby resisted killing when he was possessed, and suggests that he let Lucifer take him over long enough to get Lucifer into the cage. Bobby insists that what he did was one-in-a-million and Sam can't take back control from Lucifer himself. Sam insists he's strong enough but Bobby doesn't believe it.
Crowley and Dean go to Niveus and Crowley kills the human guards to get inside. Angry, Dean runs in but Crowley is unimpressed. He then sends Dean up in the elevator with the instructions, warning him to be convincing, while he stays behind. Dean fights his way past the demons to Brady's office. He offers Brady the two Horsemen rings, but the demon has to come with him to get them. Brady who told Dean that he wants the rings and Dean stutters over the answer. The demon then explains that the War and Famine are withered husks that can't be restored, and he wants retribution. Brady slams Dean out into the hallway and starts beating him. Dean runs for the elevator and gets to the ground floor, but Brady is already there. Crowley puts a bag with a devil's trap over his head and then beats him unconscious. He then explains the whole thing was a setup.
As they drive back, Crowley carves a sigil to trap the demon in Brady's body. He then tells Dean that they need to go somewhere else, and finally admits that the Brady demon and Sam have history. Dean pulls over and demands answers.
The next morning, Crowley and Dean pull up. Dean takes Brady away separately and Crowley says that Sam should stay away. He refuses and goes to see Dean. Brady hears Sam and addresses him by name, and the demon explains that he had taken over Brady years ago when they were in college, and he was the one who introduced Sam to Jess. When Sam goes berserk, Dean shoves Sam out and tells him to get himself under control. Sam doesn't believe that Crowley can be trusted. Meanwhile, Crowley talks to Brady and explains that Lucifer will kill demons and humans alike. Brady doesn't believe it and figures he's dead either way, and promises that Lucifer will torment Crowley forever. Crowley walks away and tells Dean that it's going well so far. He then explains that he has to stir up some demons and teleports away.
As Dean goes to the bathroom to wash up, Sam locks him in and goes to see Brady. The demon boasts of how he slipped into Sam's life. When Sam turned into a mild-mannered college student, Brady killed Jess to get Sam back on track. Sam prepares to cut his throat with the knife and Brady dares him to do it, but Sam gets control of himself. He lets Dean out, and Dean confirms that Brady is still alive. Crowley returns and tells him that he's going to live forever. He then explains that he slaughtered all of the demons except one, and let him escape with the idea that Brady was working with Crowley, his lover. As Brady considers his options, they hear a hellhound in the distance. Crowley realizes the demons planted a tracking device on him. He tosses it to Dean and teleports away.
As Dean goes for the salt, the hellhound leaps in the window. He grabs a gun and manages to hold it off long enough to get back to Brady and Sam. Crowley returns with a hellhound of his own, and unleashes it on the other one. The two invisible beasts fight it out, while Sam and Dean get Brady to the Impala. They drive away with Crowley as the hounds finish attacking each other.
Later, Brady gives Crowley the location where Pestilence is, and Crowley figures that he's telling the truth. Once he leaves, Sam and Dean trap him in a circle of salt and Sam comes at him with the knife. Brady notes that Sam is the one who let them get to him, over and over again. Sam cuts him repeatedly and Brady taunts him, saying that the only difference between Sam and a demon is that his Hell is on Earth. Sam stabs him in the chest, and then admits it's an interesting theory.
Bobby is at home coordinating with Rufus, trying to locate Death. As he finishes his call, Crowley appears behind him. Bobby shoots him just to hurt him, and Crowley explains he's there to help him get the Death ring. He has a spell, but he needs Bobby to make a wish and offer his soul. Bobby responds by shooting Crowley again. The demon promises he'll give Bobby his soul back, and he needs to do it to save himself. Bobby considers the offer...