In an attempt to save Dean Winchester from the Mark of Cain, hacker and hunter Charlie Bradbury embarks on a search for the Book of the Damned, ultimately finding it while chased by the Styne Family. The Winchesters are unable to decrypt the Book of the Damned and Sam apparently destroys it while killing Jacob Frankenstein.
In secret, Sam saves the Book of the Damned and forges a deal with the witch Rowena MacLeod to decode the Book of the Damned and use it to remove the Mark of Cain from Dean's arm. As part of this, Sam gets Rowena Nadia's Codex, but it is also encrypted so Sam calls in Charlie and the Seraphim Castiel to help decode the codex. However, Rowena's bickering causes Charlie to flee to the Blackbird Motel for some space to herself to work on her decoder while Dean learns the truth from a captured Eldon Frankenstein before Eldon rips off his left arm and escapes the Men of Letters bunker.
At the same time that Charlie is attempting to break the Book of the Damned, Eli Frankenstein is searching for her and finally manages to track Charlie to the Blackbird Motel under the name of Carrie Asimov. Eli alerts Eldon who decides to take care of Charlie himself and rejects Eli's further help.
Moments after Charlie succeeds in figuring out how to decode Nadia's Codex, Eldon starts banging on the door of Charlie's room, demanding the Book of the Damned. Frightened, Charlie takes her Surface Tablet and retreats into the bathroom as Eldon begins trying to break down the door.
Cornered and frightened, Charlie calls Sam for help. Charlie tells Sam that she is at the Blackbird Motel and that someone is there and thinks that she has the Book of the Damned. Sam tells Charlie to give whoever is at the door the Book of the Damned if she has it, but Charlie tells him that all she has is her notes.
As Charlie talks to Sam on the phone, she begins uploading her notes into an email to Sam. Sam desperately tells Charlie to give Eldon her notes or anything else she has before Dean takes the phone and reiterates Sam's order. As Eldon breaks in, Charlie sadly tells Dean that "I can't do that Dean." As Eldon searches the room, the upload finishes. Charlie sends the email with her notes to Sam and then destroys her computer, smashing it against the bathroom sink so that Eldon can't gain access to her work.
Drawn by the noise of the computer breaking, Eldon enters the bathroom where he demands that Charlie give him what's his and his family. In response, Charlie bravely raises a knife to defend herself, amusing Eldon. Charlie loses the fight that follows and Eldon stabs Charlie, several times, killing her. Eldon then departs, leaving Charlie's body in the bathtub.
By the time the Winchesters arrive at the Blackbird Motel, Charlie is dead and Eldon is gone. Charlie's death devastates the Winchesters who give her a Hunter's Funeral, burning Charlie's body in true hunter tradition. An enraged Dean goes on to massacre the American branch of the Styne Family in revenge, avenging Charlie when he kills Eldon at the end of the massacre.
At Charlie's funeral, Dean orders Sam to put an end to his work on the Book of the Damned and removing the Mark of Cain. Charlie's murder initially causes Sam to agree, but after Sam receives Charlie's email with the decoder Charlie created before she died, Sam changes his mind when Rowena confirms it can crack the Book of the Damned.
Almost three years later, after encountering an alternate reality version of Charlie, Dean becomes determined to rescue her from the angels. Dean explains to Arthur Ketch about Charlie's murder and how he still feels guilt over his inability to have saved Charlie and his hopes that saving her counterpart will alleviate some of that guilt. Wishing to make up for some of his own sins, Arthur agrees to help Dean after hearing the story.
- Charlie's murder pushes Dean further under the influence of the Mark of Cain. It causes Dean to massacre the American branch of the Styne Family in revenge, even Cyrus who hates his family and is not evil. At least twenty people are killed by Dean in revenge for this one act.