Pittsburgh, 1996. Jamie (Jake Gyllenhall) is seen working in an electronics store. He's talking and flirting with women of all ages into buying phones and stereos while flirting with the store owner's girlfriend, Christy. Jamie and Christy sneak into the back to have sex and she accidentally calls her boyfriend on the intercom phone and he hears them everything. After getting punched in the face by his boss, Jamie runs out of the store (stopping to flirt with a woman, named Amber, on the way out).
Later that night, Jamie is at his parents house for dinner. His father and his sister are doctors and his bumbling 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.
With Josh's help, Jamie goes to work for Pfizer after he attends several seminar classes. After that, Jamie goes out 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 business partner and supervisor Bruce (Oliver Platt) who sees Jamie as his ticket to the "big leagues" of Chicago so Bruce can be 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 medicine cabinets to steal all of the Prozac samples and throw them in the dumpster.
Over the next few days, Jamie is still unable to raise his sales so he pays Dr. Knight a bribe of $1,000 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 Jamie (wearing a white lab coat) pretends to be an intern. Knight's patient is Maggie (Anne Hathaway) a 26-year-old woman diagnosed with an early onset of Parkinson's Disease. Maggie tells Jamie that someone broke into her house and stole all her medication and she gives him a long list of refills that she needs. While there, Maggie asks Dr Knight, while Jamie looks on, to 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 the Prozac medication that he stole from Dr. Knight's medicine closet, and punches him in the face for pretending to be an intern and for looking at her breast. She takes his picture with an instant camera and leaves.
Jamie comes home to find Josh who has split from his wife and wants to stay with him for a few weeks while he finds a place to live. Jamie calls Dr. Knight's receptionist (who he is sleeping with) and gets Maggie's address and home phone 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 apartment and have very casual 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 and whenever she calls him. Maggie even once shows up one night at Jamie's apartment, stark nude under a coat for sex, only to have Jamie's brother/roommate Josh, wakening where he was sleeping on the living room couch, see all of her.
Later at work, Jamie is throwing away the Prozac pills in a parking lot dumpster when he looks up to get punched in the face by Trey (Gabriel Macht), the hot-tempered 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 gets take-out food and goes to see Maggie at her downtown loft. After briefly discussing Trey (he's married but was seeing her on the side) and Maggie's Parkinson's (she's a waitress in a small coffee shop and has no health insurance) they start to have sex but Jamie is unable to get erect for the occasion. After a few kind words from Maggie, they just hang out and she teases him that he should use some new erection drug that his company has developed. The next day before Jamie leaves, Maggie begins having problems with tremors in her left hand, 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.
At work, Jamie gets the green light to sell Viagra and suddenly he is extremely popular and the doctors pursue him.
Back at his apartment, 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 does come back Maggie is touched that he waited for over 24 hours. Maggie 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 after having another round of hot and heavy sex, Maggie talks about how she use to be a painter but since her diagnosis with Parkinson's, she has switched to photography/collages. Jamie talks about how he dropped out of med school because he has ADD (Attention Deficit Disorder).
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 because of her illness. 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 of water against a wall for she cannot stop her tremors in her left hand. 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 by a woman, who sees her hand tremors, to a Parkinson's convention across the street. She is moved by the people (mostly elderly and middle aged) and their stories about dealing with Parkinson's. Maggie texts Jamie to come over and join her. While at the refreshment table, Jamie meets and talks with a middle-aged man whose wife is in the final stages of the disease (stage 4). Jamie asks for advice and the man tells him to make a run for it. The man tells Jamie that he should not be in a relationship with a person with an incurable disease which will lead to a major heartache for both parties as well as his financial ruin over medical expenses as Maggie (whom still is in stage 1 of Parkinsion's) will get sicker and sicker with uncontrolable body twitches which will lead to her slow death. This shakes Jamie and, after the convention, Maggie tells him how much she loves him and how happy she is that she found out about the Parkinsons conference and that he is with her now that she no longer has any fear about what her Parkinson's will do. Jamie is beside himself, barely able to hide his insecurity.
In a montage, we see Jamie researching all about Parkinson's Disease on the Internet and at various medical libraries and pushing Dr. Knight for info on specialists to help her find a cure or at least slow the progress of the disease. Over the next few weeks, Jamie starts taking Maggie to specialists and seminars across the country, paying for her to have tests done and maxing out his credit cards on hotel rooms and airfares. At one doctor's office in Boston, Jamie gets angry with a receptionist because their appointment was re-scheduled and they had flown in to see the doctor for only that one day. 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 Parkinson's and that she isn't having fun anymore. They break up against Jamie's wishes.
Jamie is depressed over his breakup with Maggie, but Dr. Knight talks him into going to a pajama 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 female co-workers. 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 at a restaurant and runs into Maggie who is on a date with some rebound guy. 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 didn't get promoted and that he just received a raise. Jamie goes home and starts to pack to move to Chicago 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 chases 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 okay 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.
In the final shot, there is a image of a video of Jamie talking about living everyday to the fullest and how "money isn't everything and you should follow your dreams".