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In the year 1996, Jamie (Gyllenhaal), who works at an electronics store, is fired for having sex with his manager's girlfriend. After his parents find out, his wealthy brother Josh (Josh Gad) offers to find him a job as a pharmaceutical sales representative. Jamie goes to work for Pfizer and tries to get doctors to prescribe Zoloft and Zithromax. He is rebuffed constantly much to the dismay of his partner Bruce (Oliver Platt), who sees Jamie as his ticket to the "big leagues" of Chicago. Bruce tells Jamie if he can get Dr. Knight (Hank Azaria) to prescribe Zoloft instead of Prozac, all the other doctors will follow his lead. Jamie uses his skills as a womanizer to gain access to Dr. Knight through his female staff.



Jamie meets one of Knight's patients, Maggie Murdock (Hathaway), who suffers from early onset Parkinson's disease. Jamie arranges a date with her, which lasts only minutes before they return to her apartment and have sex.



In the hospital parking lot, Jamie is beaten up by the top-selling Prozac rep Trey, also one of Maggie's ex-lovers, who warns Jamie to stay away from her and the doctors. That night, Jamie goes to Maggie's apartment, and they start having sex but Jamie is unable to get an erection. Maggie teases him that he should use the new erection drug, Viagra, that his company has developed. Jamie starts selling Viagra, which becomes very popular with the doctors.



Jamie tries to convince Maggie to have a fuller relationship with him, but she refuses. The next day, Maggie is helping senior citizens onto a bus bound for Canada to get cheap prescription drugs when Jamie shows up. They argue about their relationship and she leaves. Jamie waits in the parking lot, and the next day when the bus comes back, Maggie is touched that he waited and tells him she will have a relationship with him.



Jamie and Maggie start spending a large amount of time together and eventually Jamie spends nights at Maggie's apartment. One night, when Jamie returns to Maggie's apartment from a bar where he was promoting Viagra, he tells Maggie that he loves her although he had never said it to anyone in his life, including his family. This astounds both Jamie and Maggie, resulting in Jamie having a slight panic attack and Maggie trying to calm him down by saying that she "said I love you to a cat once". Maggie's comment does in fact calm him and so he asks for her to hold him.



The next morning, Jamie stumbles in on his younger brother masturbating to a sex tape that he and Maggie had filmed previously. Josh apologizes and tries to make excuses but Jamie is angered and shocked either way.



Jamie asks Maggie to go to a medical conference with him in Chicago. While at the conference she is invited to a Parkinson's convention across the street. She is moved by the people and their stories. She asks Jamie to come over and join her and he meets a man whose wife is in the final stages of the disease. Jamie asks for advice about Maggie, and the man tells him to run. This shakes Jamie. After the convention, Maggie tells him how much she loves him.



Jamie starts researching Parkinson's and pushing Knight for information on specialists. He starts taking Maggie to a specialist and paying for her to have tests done. At one office Jamie becomes upset because their appointment was rescheduled after they had flown in to see the doctor. While Jamie is yelling at the receptionist, Maggie walks out. They fight and Maggie says there is no cure. Maggie sees that Jamie can only love her with the hope that one day there will be a cure, and so she breaks up with him.



Some time later, Jamie goes to meet Bruce for dinner and runs into Maggie, who is on a date. Bruce shows up and says that Jamie has been promoted to the Chicago office. Jamie goes home and starts to pack but realizes he wants to be with Maggie and goes to the diner where she works. Her boss tells him she has left for Canada to obtain drugs and Jamie goes off after her. Jamie flags down the bus Maggie is on. Maggie gets off and says that Jamie has five minutes to talk. He tells Maggie about how she makes him a better person, that he loves her and needs her. She starts to cry and says she will need him more. The film ends with Maggie and Jamie living together with Jamie refusing the Chicago promotion, and enrolling in medical school.
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