Dean is on the road and calls Ellen to see if she's had gotten any word from Sam, as he has no idea where his brother is. As he talks, Sam calls and asks Dean to meet him. Dean drives to Twin Lakes and arrives at a motel room. The door is unlocked and Sam is inside, his hands and shirt covered in someone else's blood. Sam admits that he doesn't remember anything.
Later, Dean returns with food after checking at the front desk and learning that Sam checked in two days ago and hasn't been seen doing anything unusual. Sam wonders if he might have hurt someone, and suggests that what happened to him may be what John warned Dean about. The last thing Sam remembers is being in a motel in West Texas, after Dean left to get burgers. They try to retrace Sam's steps and Dean notices blood on the window handle. They go outside into an alleyway and Sam says that it feels familiar. There are several apartment garages nearby, and Sam finds a key to one of them in his pocket. Inside is an old Volkswagen and more blood inside. In the back seat is a knife, also covered in blood. There's also a pack of cigarettes and a gas receipt for a station a few cars over.
The brothers drive to the station and talk to the clerk on duty. He tells Sam to get out, and says that he came in drunk and start drinking malt liquor, then threw the bottle at the clerk. Dean tells Sam to wait in the car and then confirms that Sam smoked and drank. He pays the clerk for the damages, and the clerk "remembers" that Sam went north out of town.
As they drive along the road out of town, Sam tells Dean to pull off on a side road. They follow the road and come to a house. Security lights come on as the brothers go to the front door. Sam spots a front window with broken glass, and a deactivated security systems. They get in and confirm that someone has torn up the interior, and then find a man's corpse. His throat has been cut, and Sam figures that he did it. Dean says that if Sam did it, he had a reason, and confirms the man didn't have any ID. Sam finds a cabinet of weapons and magical sigils, and they figure the dead man was a hunter. They check the man's security tapes and confirm that Sam broke in, beat the hunter, and then killed him.
As Dean cleans up the place, Sam finds a letter from the hunter's daughter to her father, Steve Wandell. Dean gets his brother back to the motel and says they'll leave town in the morning, but Sam says that he killed Wandell. He explains that for the last few weeks, he's been having feelings of rage, and they've been getting worse. He didn't tell Dean because he didn't want to scare him. He figures the Yellow-Eyed Demon is forcing him to become a killer, like he has the other psychic children. When Sam says that Dean has to kill him to keep his promise, Dean says that there has to be another way. Sam gives him a gun and tells him to kill him before he hurts anyone else. Dean refuses and Sam knocks him out and then goes.
Dean wakes up later when the manager arrives to tell him it's past checkout. He confirms that Sam left before dawn, and Dean asks to use his computer. He pays the manager to use his computer, and then calls to activate the GPS in Sam's cell phone. It indicates that he's in Duluth, MN, and heads out.
Sam arrives at a tavern in Duluth and talks to the bartender: Jo Harvelle. She asks why he's there, given they parted on bad terms, and Sam say he's there to square things. She notices a burn on his right arm, but Sam discusses it as an accident. He then says that John as obsessed with hunting and didn't care about others, but says that's not him. Jo asks him about Dean, and Sam admits that Dean is more like John. He then realizes that Jo has feelings for Dean, and tells her that Dean doesn't think of her romantically. He takes her hand and says that he cares about her, and she asks what's going on. Sam says he can be more to her and then lets go of her hand, but then grabs her and stops her when she tries to hit him with a bottle and knocks her out.
Sam ties Jo up and asks what Ellen told her about her father Bill's death. She figures that Sam isn't Sam, but he insists that he is and invites her to talk. Jo tells him about how John used her father as bait, got eager and leaped out early, and exposed her father to the monster. Sam tells her that the monster hurt her father but didn't kill him, and John did to put Bill out of his misery. When she asks why he's doing this to her, Sam explains that she's bait. Dean barges in and Sam holds the knife to her throat, and then tells Dean to kill him before he kills Jo. Dean hesitates and then lowers the gun, and then throws holy water into Sam's face. It burns, and Sam leaps out the window. Dean cuts Jo free and then goes out after him.
Dean follows his brother into a nearby warehouse and calls out, asking the demons what it is. It says that it has many names, and didn't kill him because it would have been too easy. The whole thing was a test to see if it could push Dean into killing Sam. It warns Dean that he can't hurt it without killing Sam. The demon plans to use Sam's body to get close to other hunters and kill them, once it finishes off Dean. Dean spots it going out a door and follows it out onto the dock, The demon gets behind him and shoots, and Dean falls into the water.
Jo follows the trail to the warehouse and tries to call Dean. She follows the tone to where Dean has crawled up on the dock and gets him back to the bar where she can tend his injured shoulder. Jo asks how Dean knew Sam was possessed, and he says that he didn't, but he knew it wasn't Sam. She then asks if demons ever tell the truth, and he says they do if it'll mess with their victims' heads. Dean figures the demon will head for the nearest hunter in South Dakota, and starts to go. Jo says she's going with him, but Dean says that it's his fight and he'll tie her back up if he has to. When she gives in, Dean promises to call her later, but Jo figures that he won't.
On the road, Sam calls the hunter. The demon is already there, and cuts the line. He then knocks on the door, and Bobby Singer lets him in. The demon claims that Sam was working a job nearby and stopped in to see him, and that Dean is hole dup with a girl. They share a toast to John and the demon takes a drink, and then spits as its mouth burns. Bobby explains that he put some holy water in the beer, and then punches the demon unconscious.
Dean arrives and helps Bobby put Sam's body in a devil's trap, and then wakes him up. The demon dares him to harm Sam's body, and Dean throws a bucket of holy water on Sam's body. As the demon sizzles, Bobby begins the exorcism and Dean says that he'll kill every demon before they can get Sam. The demon laughs and says that it doesn't care about the master plan, and then points out that the exorcism ritual isn't working. It boasts that it knows a few tricks of its own and utters a chant, and the room explodes in telekinetic fury. Bobby sees the burn and realizes that it's a binding link. He explains that the demon has locked itself inside of Sam, and he doesn't know what to do. The ceiling cracks, breaking the devil's trap, and then telekinetically slams Dean and Bobby into the walls. It rips free of its bonds and starts beating Dean, who realizes that it's Meg. Meg says that it had to claw its way out of Hell, where John is held captive, and says that Dean knows he's worthless because he failed to save John, and he'll fail to save Sam. Bobby comes up behind him and uses a hot poker to burn the binding link, releasing the demon. The demon smoke flees through the fireplace, and Sam asks if he missed anything. Dean hits him once, hard.
Later, the brothers recuperate and Bobby tells them that hunters are looking for Wandell's killer. Dean and Sam insist that they haven't heard of him, and Bobby warns that the hunters won't listen to reason. As they brothers leave, Bobby gives them charms to prevent possession and tells them to be careful. As the brothers hit the road, Sam explains that he was awake during some of what happened, and he remembers killing Wandell. When he points out that Dean didn't kill him as he promised, Dean says that he only promised to do it if he couldn't save Sam... and now he's going to save Sam no matter what it takes. Dean then laughs and points out that Sam had a girl inside him for an entire week.