The movie opens showing Jamie (Jake Gyllenhall) working in an electronics store in the 90’s. He’s talking females of all ages into buying phones and stereos while flirting with the store owner’s girlfriend. Jamie and the owner’s girlfriend sneak into the back to have sex and she accidentally calls her boyfriend and he hears them everything. After getting punched in the face by his boss, Jamie runs out of the store (stopping to hit on a woman on the way out).
Later that night we see Jamie at his parent’s house for dinner. His father and maybe his sister are doctors and his brother Josh is rich from owning a medical software company. At dinner Josh and his wife fight and he brings up Jamie getting fired and the family gets on him for dropping out of med school. Jamie blows them off and brings up that Josh is going to help him get set up as a pharmaceutical sales rep.
Next is a montage of Jamie going to work for Pfizer, practicing his sales pitch and trying to get doctors to prescribe Zoloft and Zithromax. He is rebuffed constantly by doctors much to the dismay of his partner Bruce (Oliver Platt) who sees Jamie as his ticket to the “big leagues” of Chicago near his wife and kids. Bruce tells Jamie if he can get Dr. Knight (Hank Azaria) to prescribe Zoloft instead of Prozac then all the other doctors will follow his lead. After trying to chat Dr. Knight up several times unsuccessfully, Jamie flirts with his receptionists and sneaks into the back to steal all of the Prozac samples and throw them in the dumpster.
Jamie is still unable to raise his sales so he pays Dr. Knight $1000 to let him shadow him. The doctor accepts and Jamie spends the day babbling about how Zoloft is better than Prozac.
Dr. Knight goes in to see a patient and tells Jamie to say he’s an intern. Knight’s patient is Maggie (Anne Hathaway) an early onset Parkinson's patient. Someone broke into her house and stole all her meds and she gives the doctor a long list of refills that she needs. While there she has the doctor look at a weird lump on her breast, which turns out to be a spider bite.
Later in the parking lot Maggie stops Jamie while he is throwing away Prozac and punches him in the face for pretending to be an intern and for looking at her breast. She takes his picture and leaves.
Jamie comes home to find Josh who has split from his wife and wants to stay with him. Jamie calls Dr. Knight’s receptionist (who he is sleeping with) and gets Maggie’s number. He calls Maggie and asks her out for coffee. At first she says no but then she gives in and meets him. The date is basically him being charming and her being rude. After 10 minutes they head back to her place and have sex. Afterwards she kicks him out right away and we see a montage of Jamie getting booty calls and him and Maggie having sex everywhere.
Later at work we see Jamie throwing away Prozac and he looks up to get punched in the face by Trey (Gabriel Macht), the rep for Prozac. Trey is the top seller in the region and gives the doctors and staff big kickbacks (trips to Florida and Hawaii) for pushing Prozac. He says he knows what Jamie is doing and that he will take him down if he doesn’t stop. Trey and Jamie fight some more and he leaves Jamie on the ground after telling him to stay way from Maggie. Jamie then gets take out food and goes to see Maggie.
After briefly discussing Trey (he’s married but was seeing her on the side) and Maggie's Parkinson’s (she’s a waitress and has no insurance) they start to have sex but Jamie is unable to rise for the occasion. After a few kind words from Maggie they just hang out and she teases him that he should use the new erection drug that his company has developed. The next day before Jamie leaves we see that Maggie is having problems with tremors, which she hides from him as she pushes him out the door. Jamie approaches Bruce about the new drug and Bruce says he will look into it.
Jamie gets the green light to sell Viagra and suddenly he is extremely popular and the doctors pursue him.
Back at his place Maggie and Jamie talk and he tries to convince her to have a relationship with him. She says no and leaves. The next day, Maggie is helping senior citizens onto a bus to go to Canada to get cheap prescription drugs when Jamie shows up. They argue about their relationship some more and she leaves. Jamie waits in the parking lot for her to come back and the next day when the bus comes back Maggie is touched that he waited. She tells him that she will have a relationship with him but that she gets to hate him and slam him to her girlfriends when he dumps her.
Back at her apartment Maggie talks about how she use to be a painter but since her Parkinson’s she has switched to photography/collages. Jamie talks about how he dropped out of med school because he has ADD.
One night after networking at the bar Jamie comes home and starts to mess around with Maggie when he starts to hyper ventilate and tells her that he loves her and that she is the first person he has ever told that to.
A few days later Bruce and Jamie are talking about an upcoming conference in Chicago and Jamie says he doesn’t want to leave Maggie to go. Jamie comes home to find Maggie drunk. Earlier in the day she realized that she ran out of meds and couldn’t get to the pharmacy in time to get a refill due to the wait in the clinic. They have a fight and Jamie leaves. After he walks out Maggie starts to cry and throws her glass. Jamie comes back and holds her and they make up.
Jamie asks Maggie to go the conference with him. She accepts and while at the conference she gets invited to a Parkinson's convention across the street. She is moved by the people and their stories. She texts Jamie to come over and join her and while at the refreshment table he meets a man who’s wife is in the final stages of the disease. Jamie asks for advice and the man tells him to run, that he wouldn’t do it again. This shakes Jamie and after the convention Maggie tells him how much she loves him and how happy she is that he is with her.
It’s montage time again. We see Jamie researching Parkinson's and pushing Dr. Knight for info on specialists. He starts taking Maggie to specialist and seminars, paying for her to have tests done and maxing out his credit cards on hotel rooms. At one office Jamie freaks out on the receptionist because their appointment was rescheduled and they had flown in to see the doctor. While he is yelling at the receptionist Maggie walks out and Jamie runs after her. They fight and Maggie says that there is no cure for her and that she isn't having fun anymore. They break up against Jamie's wishes.
Jamie is depressed but Dr. Knight talks him into going to a pj party at another doctor’s house. Jamie and Josh show up and Josh hooks up with someone right away. Jamie takes Viagra and has a three-way with two coworkers. Jamie wakes up later in pain and sees that he is having a bad reaction to the Viagra. As his brother drives him to the ER, Josh tells him that he doesn’t envy Jamie's random empty sex life and that he misses his wife and he is going back to her.
The next night Jamie goes to meet Bruce for dinner and runs into Maggie who is on a date. After some awkward conversation Bruce shows up and says that Jamie has been promoted to the Chicago office. Maggie congratulates him and hurries off.
During dinner Bruce tells Jamie that he also didn’t get promoted that he just received a raise. Jamie goes home and starts to pack when he finds a video that he and Maggie had made of their talking in bed. He realizes that he wants to be with Maggie and goes to the dinner where she works.
Her boss tells him that she has left for a med run to Canada and Jamie speeds off after her.
Jamie flags the bus down on the highway and gets them to pull over at a rest stop. Maggie gets off and says that Jamie has three 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 that she will need him more. He says that’s ok and she says she can’t ask that of him. He says “you didn’t” and tells her that even if in some alternate reality there was a healthy version of both of them with no worries or problems that he would still choose their reality and problems. They hug and kiss and the movie cuts to yet another montage with a voice over from Jamie. It shows Maggie and Jamie living together and Jamie studying for med school.
The movie ends with a video of Jamie talking about living everyday to the fullest and how money isn't everything and you should follow your dreams.
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