After the Apocalypse was averted and Lucifer was locked in his Cage once more, the demon Crowley formed an alliance with the angel Castiel in order to secure his place as King of Hell while allowing Castiel to defeat the archangel Raphael by finding Purgatory and taking in all the souls there as a power source. Crowley searched by resurrecting hunter Samuel Campbell and making a deal with him before he and Castiel faked his death when the Winchesters raided his prison for monsters. Crowley's survival remained undetected for months, allowing him to operate in secret before Eve revealed that Crowley was still alive to the Winchesters when they confronted her. After finding out, the Winchesters began hunting down answers which led them to discover Castiel's involvement. After being captured in a ring of Holy Fire, Castiel confessed his involvement, but refused to stop his plan to find Purgatory despite the pleas of Dean.
As Castiel refuses to work with him if harms the Winchesters directly, Crowley sends two demons to kidnap Lisa and Ben Braeden, Dean's ex-girlfriend and her son. One demon breaks through the front door of Lisa's house and grabs her while her new boyfriend Matt tries to convince the demon to let her go. Hearing the commotion, Ben comes downstairs in time to see the second demon sneak up behind Matt and snap his neck, killing him. Hiding in his room, Ben quickly calls Dean and lets him know what happened. Ben is unable to give Dean any clues as to what is after him and Lisa, nor is he able to reach a shotgun Dean left in Lisa's closet so Dean tells him to jump out of his bedroom window, but before he can make it out, the demons kick down his door and capture him. Crowley then picks up Ben's phone and reveals himself to Dean, telling him that he is going to hold Lisa and Ben hostage to ensure the Winchesters stay out of his business, promising not to hurt them if Dean does as he says.
Refusing to do as Crowley wants, Dean has Bobby investigate a new angle on the search for Purgatory while he and Sam summon the angel Balthazar for help. Dean tells the annoyed Balthazar that Crowley is alive, but Balthazar already knows as Castiel had informed him already. The Winchesters inform Balthazar of Castiel's deal with Crowley which surprises him as Balthazar didn't know about it. Dean asks for Balthazar's help in finding Lisa and Ben, but after asking why he should help, Balthazar simply teleports away. Sam presses Dean to call upon Castiel for help, suggesting that he doesn't know what Crowley is doing with Lisa and Ben, but Dean refuses to hear of it.
Needing another idea, Dean begins capturing demons and torturing them inside of a devil's trap painted inside Bobby's shed. Once he's satisfied that he can't get anything out of them, Dean kills the demons. As Dean starts working on his fourth demon, Sam tries to get him to take a break, but Dean refuses as he knows that whatever's happening to Lisa and Ben is his fault. Leaving the shed, Sam prays to Castiel to help them if he has any heart at all, not noticing that Castiel is watching him invisibly.
Castiel confronts Crowley about his actions as he had demanded that Crowley leave the Winchesters alone. Crowley tells Castiel that he's exploiting a loophole by kidnapping Lisa and Ben since the Winchesters will now be scouring the Earth for the two rather than focusing on stopping the two of them from finding Purgatory. Castiel demands to know where Lisa and Ben are, but Crowley refuses to tell him and tells Castiel to find Purgatory. Before the two can argue any further, Castiel is contacted by Balthazar and leaves to meet with him.
Appearing in a forest, Castiel meets with Balthazar who demands to know if Castiel is working with Crowley. Though Castiel lies about it, Balthazar is able to tell and Castiel explains that him working with Crowley is a means to an end. Balthazar asks if the plan is for Castiel to suck all the souls out of Purgatory into himself which Castiel confirms, stating that its the only way to win the war against Raphael. Balthazar points out that if Castiel can't control the power he absorbs, it will cause catastrophic damage to the planet and asks for a reassurance that the plan is safe. Castiel simply asks for his allegiance and Balthazar gives it, telling Castiel that the Winchesters were the ones who informed him of the Purgatory plan and are angry about the kidnapping of Lisa and Ben.
As Dean continues to torture the fourth demon he captured, he accidentally breaks the devil's trap and the demon flings him against Bobby's van. The demon strangles Dean, but before he can kill him, Castiel appears behind the demon and smites him, saving a shocked Dean. Despite being saved by him, Dean is displeased to see Castiel who tells Dean that he didn't know Crowley would take Lisa and Ben. Dean refuses to believe Castiel who asks Dean to trust him, reminding Dean that he does everything Dean asks, he always comes when Dean calls and he just saved him again despite Dean's lack of faith in him and his threats. Castiel asks Dean to trust his plan, feeling he's earned that much from him. Castiel tells Dean he came to tell him that he will find Lisa and Ben and bring them back, but he asks that Dean stand behind him the one time that Castiel asks it of him. Dean sees this as Castiel giving him the "same ransom note" as Crowley and refuses to listen, telling Castiel to go back to Crowley and tell him "you can both kiss my ass." After a moment, Castiel reluctantly honors Dean's wishes and leaves.
That night, Balthazar comes to Bobby's house and reveals that he's decided to side with the Winchesters. He explains that Castiel is too sure of himself for "someone who is about to swallow a million nuclear reactors" and too many things can go wrong with his plan. As a result, Balthazar is now willing to work as a double agent for the Winchesters and took the liberty of finding Lisa and Ben for them. Balthazar tells Sam and Dean he found them, but he can't get in and get them out as Crowley put up angel warding, presumably as a precaution against Castiel. Balthazar agrees to take the Winchesters to Lisa and Ben's location, but tells them that they are on their own after that.
Balthazar teleports the Winchesters outside of the warehouse where Lisa and Ben are being held and wishes them luck before teleporting away again. Spotting a guard coming outside, Dean kills him with the demon-killing knife before he and Sam enter the building and split up to look for Lisa and Ben. As he searches, Sam is knocked out by a demon guard and locked in a room by his attacker and another demon.
In the room Lisa and Ben are held in, the three demons guarding them hear signs of a struggle and leave the room only to face Dean who kills them and sends two of their bodies back inside. Dean cuts Lisa and Ben free, but Lisa grabs the demon-killing knife and uses it to take Ben hostage, revealing that Lisa is possessed by a demon. The demon explains that Crowley figured that Dean might come and had the demon possess Lisa for insurance. The demon taunts Dean and Ben about things it claims Lisa feels about them both before Dean splashes it in the face with holy water, forcing the demon to release Ben. Dean engages the demon briefly, disarming it of the knife which Dean kicks to Ben. The demon taunts Dean when he hesitates to continue to fight, not wanting to hurt Lisa. Rather than continuing to fight the demon, Dean starts an exorcism, causing the demon to punch him in the face in an attempt to stop him. Dean continues his exorcism even as the demon chokes him so the demon picks up a straight razor and forces Lisa to stab herself in the stomach, telling Dean that he exorcises it, Lisa will die. After a moment's hesitation, Dean continues his exorcism and exorcises the demon out of Lisa and back to Hell, causing Lisa to collapse.
Finding Lisa still alive though in bad shape, Dean tries to call the still-unconscious Sam. Unable to reach his brother, Dean slaps Ben who is in shock to snap him out of it and tells him to grab his shotgun since Dean needs to carry Lisa outside, meaning that if anything comes after them, Ben will have to shoot it. Making their way out of the warehouse, they encounter a few demons who Ben takes down with Dean's shotgun. Hearing Sam's cries for help, Dean frees his brother who steals a car and rushes them to the nearest hospital.
At the hospital, Lisa's wounds are determined to be mortal and a grieving and angry Ben leaves Dean before Castiel appears. Dean refuses to listen to Castiel's apologies for his actions since Lisa will die soon and Dean feels that its too little, too late. Telling Dean he didn't come for him, Castiel heals Lisa's wounds to Dean's surprise and tells Dean that Lisa will now wake soon and survive. Castiel insists that he meant it when he told Dean he was sorry and Dean thanks him with both wishing that Castiel saving Lisa changes things. Castiel tells Dean that he wanted to at least fix what he could for Dean who asks him to erase Lisa and Ben's memories of him to keep them safe. Castiel complies with Dean's wishes and a story is invented that the two were in a car crash to explain Lisa's presence in the hospital. Dean pretends to be the person who hit their car so he can say sorry and a final goodbye though neither Lisa nor Ben recognize him anymore.
After Lisa and Ben's memories are erased, Sam disagrees with how his brother handled the situation, but Dean refuses to hear anymore about it and orders that Sam never talk to him about Lisa and Ben ever again.
After helping save Lisa and Ben, Castiel fully turns against the Winchesters in his continuing quest for Purgatory to the point where he shatters Sam's wall to keep him and Dean out of the way. Balthazar, while he has some doubts, aids the Winchesters in finding where Castiel and Crowley are doing their ritual to open Purgatory, but is found out by Castiel and killed.
- During the rescue, Dean performs an exorcism on Lisa. This is one of only four times Dean performs an exorcism and the first Dean completes one on his own. It is also the only time that Dean performing a full exorcism is shown. In Crossroad Blues, Dean stopped before finishing his exorcism and in Swap Meat, he performed one alongside teenage witch Gary Frankle. In Repo Man Dean is only briefly seen performing an exorcism in flashback.
- The demons that actually kidnapped Lisa and Ben and killed Matt are both killed during the rescue. These two demons are two of the ones guarding Lisa and Ben directly and the one that killed Matt is the final one Dean killed during the rescue.