Police break into a home and find a young woman tied to a chair and badly injured. As they free her, she tells them that her attacker is in the next room, and when they pursue him, it is revealed to be none other than Dean Winchester (Jensen Ackles
One week previously, Sam (Jared Padalecki
) receives an e-mail from a college friend, Becky, saying that her brother Zach was arrested for murdering his girlfriend, but that she is sure he is innocent. Despite Dean's doubts, the brothers immediately travel to St. Louis and meet up with the girl, who swears that Zach was with her at the time of the murder and says he could not have been in two places at once. Sam lies that Dean is a detective, and they go to investigate the crime scene, where they learn that someone broke in and stole some clothes prior to the murder, and that there was no sign of forced entry. Rebecca admits she stole the security tape that seems to prove Zach's guilt, and when Dean and Sam watch it, they notice that Zach's eyes flare unnaturally in the cameras glow, suggesting that it is not really him.
Elsewhere, Zach spies on a happy young couple. Later that night, the man returns to his home to find his wife tied up and bloodied, and she pleads with him not to hurt her "anymore." When he explores the house, he encounters someone that looks exactly like him, who then knocks him out. As Sam and Dean look for a trail at Zach's house, they see the ambulance speeding by and learn about the couple's case, extremely similar to Zach's, in which the alleged perpetrator was in two places at once. They speculate that they are dealing with a shapeshifter, and note that the trail ends abruptly, suggesting it either flew away or used the sewers. As they explore underground, they find disgusting piles of skin and blood, leading them to conclude that the shifter sheds when it changes its form. Dean states that a silver bullet to the heart will kill the shifter, and checks the arsenal in his car trunk. Sam receives a call from an angry Rebecca, who has learned that Dean is not actually a cop, and she tells them to stay away from her and the case. They continue searching for the shifter's lair and are ambushed by the creature in the sewers. They split up to try to find it, but when they meet up again, Dean's eyes flare momentarily, revealing that it is really the shifter. Sam catches on quickly and threatens to shoot him, but he hesitates and the shifter overpowers him.
Sam awakens to find himself tied up and demands to know where his brother is, but the shifter, still in Dean's form, seems to be "downloading" Dean's thoughts and memories as well as his appearance and tells Sam that Dean is jealous and resentful because Sam escaped the hunter life for college. The shifter then goes to Rebecca's house to explain about the lies, and ends up telling her part of the truth about the shifter's existence, saying it is a creature that was "born different" and was hated until it learned to change form, and now just wants to be loved. He makes a move on Rebecca, but she rejects him angrily and he attacks, tying her up like the other victims, and the police soon come and catch Dean in the act. He manages to fend off the cops and then escapes to an alley, where he begins his gruesome and painful transformation into another form.
Back at the lair, Sam realizes that the real Dean is captive in the room with him, and they manage to escape. They seen Dean's face on the news and realize he is a fugitive, and lament that the shifter has the Impala, as well as all the guns and weapons in the trunk. When the cops close in on them, Sam helps Dean escape and distracts them. Sam hurries to Rebecca's house to warn her--but Dean finds the real Rebecca in the creatures lair, revealing that the shifter has now taken her form. The shifter captures Sam and then takes Dean's form once again, planning to kill him, but Sam breaks free and they have a brutal hand-to-hand fight. The shifter almost overpowers Sam, but the real Dean arrives just in time and kills the shifter with a silver bullet, grimly looking down at "his own" dead body and taking his amulet necklace back.
As Dean and Sam prepare to leave St. Louis, Sam confesses the whole truth about his hunter life to Rebecca, and admits that his deceased girlfriend Jessica did not know about him, and she speculates that a hunters life must be lonely. It is revealed that the multiple murders were blamed on Dean, now presumed dead. In the car, Dean expresses the wish that Sam could have a normal life, but he dismisses this, saying they are both "freaks."