In San Francisco, Madison is drinking at a bar with her friends when her boss, Nate Mulligan, comes over and says she needs to come back to the office to do some work. She quickly realizes that he's trying to pick her up. He then tries to get her to drive him home, and she tells him that she's already called him a cab. As he stumbles off, Madison assures her friends that it happens a lot. As she turns to watch Nate go, she spots a man watching her from a nearby table. When she turns back a moment later, he's gone. Madison leaves for the night and jumps when she hears a dog digging through some garbage cans. She gets into her car and drives away, and the man from the bar watches her go.
The next morning, Madison arrives at work and notices a bloody handprint on the door to Nate's office. She goes in and finds Nate laid out on his table, his heart ripped out.
Sometime later, Sam poses as a detective arrives at the morgue and talks to the coroner, who shows him the body. She admits off the record that he was apparently attacked by an animal, and had his heart ripped out. Back at their motel, Sam tells his brother that there have been a series of murders, mostly of hookers, all taking places in the five days leading up to the full moon, and all with their hearts missing. Dean is eager to take on a werewolf, They go to talk to Madison, whose friend Glen is just leaving after dropping off a casserole. She explains that she worked for Nate for two years ago, and he was nice. When she hesitates, Sam picks up on it and Madison admits that Nate could get drunk and start hitting on women. When they ask if Nate has any enemies, Madison admits that her former boyfriend, Kurt Mueller, got possessive and attacked Nate when he thought there was something between her and Nate. She admits that Kurt was at the bar the night that Nate was killed. Outside, Dean figures they should go pay Kurt a visit.
In the house, Madison hears a dog barking and goes to the window. She sees Kurt outside, looking up at her window, but he disappears when she looks away for a moment.
Sam and Dean break into Kurt's apartment but find nothing. They hear noises outside and check, and find claw marks on the walls leading up to Kurt's apartment.
On the street nearby, a policeman hears something moving in an alleyway. A creature leaps out at him and he shoots. Dean and Sam hear the gunshot and go to investigate, and find the officer dead, viciously disemboweled. Sam calls 911 while Dean checks the body and figures that Kurt is their likely suspect. They figure that Madison is at risk and go to talk to her the next morning. Glen watches them from the next door apartment, but they tell him to go back inside. Madison confirms that Kurt was there the previous night, and Dean figures Sam should go check Kurt out. Sam disagrees, and wins at Rock-Scissors-Paper so that he stays and watches over Madison.
Sam nervously remains in the kitchen, even when Madison invites him to sit on the couch. She finally gets him to move by sorting her underwear on the kitchen table in front of him. Dean calls and tells Sam that Kurt hasn't shown up at work in a week, but he's got a line on where he is. He also figures that Sam hasn't even spoken to Madison yet. When Dean asks what Madison is wearing, Sam quickly hangs up. Madison then sits down on the couch next to Sam and turns on the TV, and she insists on watching soap operas. By the end of the day, Sam is hooked. He asks Madison why she's with Kurt when she's clearly smart and independent, and she admits she was too insecure to leave. She explains that she got mugged and it rattled her, but she decided to take control of her life and dumped Kurt. Sam compliments her, saying she's unusual in a nice way. Dean calls to say that he's tracked Kurt to a strip bar and is eager to stay as long as it takes.
That night, Madison tells Sam that she's going to bed. He awkwardly wishes her good night and settles down to watching the television.
Dean keeps watch outside of Kurt's apartment and hears the sound of breaking glass. He runs in and finds Madison in a werewolf form, killing Kurt. She stuns him, but Dean manages to drive her off with a silver blade cut to her right arm.
The next morning, Dean recovers consciousness and calls Sam to tell him that Madison is the killer. Sam goes to the bedroom and confirms that she's in bed, asleep. She wakes up and is surprised to discover that she's naked, and Sam notices the cut on her right arm. He goes to the door and locks it, and says neither one of them are going anywhere. Sam ties her up, gets out a gun and waits, and Madison figures that he must be a psychotic. He dismisses her protestations as an act, but she says that he needs help. Dean arrives and Sam says they need to talk. He figures that Madison doesn't know what she is, and that she killed Nate and Kurt because the animal part of her brain thought they were threats. Dean points out that it doesn't make any difference whether she can control her killing sprees or not, but Sam proposes they try to cure her using John's theory that they kill the werewolf that bit her. He admits that he can sympathize with her as a monster, and checks with Madison to confirm that the mugger that attacked her bit her on the back of her neck. Sam then puts his gun down and checks the wound, and Madison confirms she was near where the hooker murders occurred, at Hunter's Point. He talks to Dean privately and suggests his brother stake it out while he stays with Madison, and promises to shoot her if he has to. Dean reluctantly agrees to Sam's plan.
Once they're alone, Madison begs Sam to let her go. He tells her that he's trying to help her, and if it works as planned, he'll leave and she can forget what happened.
A hooker is walking down the street when she hears a howling noise.
At Madison's apartment, the full moon rises and Madison transforms, attacking Sam.
On the streets, another werewolf comes after the hooker.
Sam draws his gun and backs up, and manages to lock Madison in the closet before she can bite her.
The werewolf prepares to kill the hooker and Dean arrives to shoot it. It's Glen, who transforms back to human as the hooker runs away in terror. He asks Dean for help and then dies.
The next morning, Madison wakes up and Sam tells her that she's back to normal and she'll never see him again. She looks at the claw marks on the closet that she made, and realizes that he's telling the truth. When she turns back to the door, Sam is gone.
Out in the Impala, Dean and Sam figure that Glen was looking to breed with Madison and spared her life. Madison comes out and asks why they're still there, and Dean admits that they're watching to make sure she doesn't turn that night. She figures they can wait together and invites them into her apartment, and admits that Sam was telling the truth. Madison blames herself for what she did, but Sam assures her that she couldn't control it. They figure that they'll have to sit with her through the night. Nothing happens and Madison hugs Sam in relief. Dean clears her throat and she thanks him as well. He takes off for the motel and Sam apologizes for tying her up. They both agree they can't go back to what their relationship was like before, and then start making love.
That night, Sam wakes up and sees a transformed Madison leaping out the window. The next morning he goes to get Dean and tells him what happened. They check with Bobby, who tells them that severing the bloodline doesn't work. Dean says that they don't have a choice anymore and have to kill her, but Sam insists they keep trying to find a cure. Madison calls them from a payphone and they pick her up and take her home. Sam insists that they'll find some answer, but Dean insists on telling her the truth that there's no cure. He offers to lock her up at night, but she could bust out and kill someone else. Madison accepts her fate and asks Sam to kill her because that's all that is left. Crying, she tells him that she wants him to do it. Dean takes the gun and Sam goes into the kitchen. His brother offers to kill her, but Sam takes the gun and says that it's his job because she asked him. He takes the gun and goes into the room, and Dean listens, shedding a single tear, as a shot rings out.
