Melissa Harper is the wife of Dan Harper.
Melissa has been with Dan ever since they were young.
One night, Dan takes Melissa out to dinner. They come back home to find their babysitter, Staci, dead.
Dean and Sam arrive the next day disguised as FBI agents. They ask Melissa if she knows anyone who would want to hurt Staci. Melissa denies this, and describes Staci as "super sweet, popular and pretty".
When Dan is later found dead at his office, Sam and Dean come back to talk to Melissa. They ask if she knew about the affair, and Melissa admits she did. She professes her love for Dan and her hopes that the two of them still had a chance. She gives the brothers her phone number, promising to call if anything strange happens. Suspecting that she might be a shapeshifter, they use a silver pen to confirm it, in which the test proved she was human.
Once the brothers have left, Melissa goes to retrieve a wooden box. She proceeds to dump all the contents into the sink. Meanwhile, she calls someone, telling them to call her back ASAP because "something went wrong".
That night, Melissa is drinking wine from a glass when someone rings her doorbell. She initially assumes it's the FBI agents. She realizes it is in fact Dan, who is supposed to be dead. "Dan" breaks into the house and goes after her. Fortunately, Melissa is able to defend herself long enough to run away.
Melissa arrives at Sam and Dean's motel room. She reveals that she had confided with her hairdresser, Sonja, about the affair, who was also a white witch. She was given a "Return to Love" spell which she completed by kissing Dan. She provides Sam with a copy of the spell. After searching on the Internet, Sam reveals that it was not a spell but a curse, known as "The Kiss of Death".
After Melissa kissed Dan, Dan went to kiss Staci which caused the death of both. Since the curse started with Melissa, it wishes to end with Melissa. When "Dan" comes back for her, Dean chooses to kiss her and thus takes the curse upon himself.
After putting some distance between themselves and the monster, Melissa notices a cache of weapons in the back of the Impala and asks what kind of FBI the boys are. The Winchesters admit that they're actually hunters, who destroy the supernatural.
Melissa later directs the Winchesters to Sonja's salon, The Art of Dyeing. Sam hands her a knife, telling her that if she sees Sonja, stabbing her will slow her down. Melissa protests that she couldn't stab anyone, but Dean reminds her that Sonja is a "wicked witch" who killed her husband and his mistress.
As Sam searches for a way to defeat the curse, the witch Sonja appears and begins suffocating Sam. Melissa arrives and provides a distraction, long enough for Sam to shoot the witch dead. The curse gets lifted when Sam stabs the heart of the Qareen.