The movie opens with Michael (Mark Duplass) & Andy (Ray Romano) in a doctor's office as she gives Michael the news that he has cancer & it has spread to several areas. She recommends he see a specialist to learn more about his prognosis and options. Andy interrupts and tries to get the doctor to give them more information about Michael's prognosis but she avoids doing this. Michael absorbs the news from the doctor without much show of emotion. The scene jumps to an abandoned drive-in theater where Michael and Andy are pulling a barrel into place to play a game. They use tennis rackets to hit racquetballs off the backside of the screen, trying to get the ball to bounce into a 55-gallon barrel they've positioned nearby. We learn later in the film they made up this game themselves and call it Paddleton. When they finish and are walking home, Andy asks Michael what he learned from the specialist. Michael ignores the question, grabs Andy's hat and runs away. Next we see them together in Andy's apartment, making a pizza then watching a movie called "Death Punch". It is obvious they've seen the movie several times as they quote lines in synch with the film and have choreographed punches and blocks as they sit side-by-side on the couch. Next there are several short scenes in quick succession; them going to work, at their jobs (Michael at a copy shop & Andy at an office), playing the game again, Michael on-line at a cancer support website, them working a jig-saw puzzle together as they watch the same movie again. As you watch their scenes together it becomes more and more obvious they really enjoy each other's company and have a very close relationship, sharing lots of inside jokes and ongoing conversations. As they are leaving another game at the theater, Andy tells Michael that he has been preparing a half-time speech to motivate a losing team that is so good he could probably sell it to a coach someday. Michael asks to hear it but Andy says it's not ready yet. Michael also unsuccessfully tries to guess the partially completed hang-man phrase on his sweatshirt that we later learn was given to him by Andy. Michael tells Andy he's seen 2 oncologists and the gist of it is that he is terminal with less than 6 months to live. He doesn't want to wait til he gets really sick and die in a hospital so he intends to use an assisted-suicide method he's discovered through the support group. He asks Andy to help him because he doesn't want to do it alone. Andy is obviously reluctant and at first tells Michael that he can't just give up. Michael explains that he doesn't want things to change between them just because of his illness, that he really just wants to continue living, doing the things they enjoy doing together until he is no longer able. At this point Andy relents and agrees that he will help. Andy investigates and finds that the closest pharmacy that will fill the prescription is 6 hours away so they decide to take a road trip. Along the drive they have interesting conversations during which we learn Andy doesn't like small talk and doesn't think he's good at it. They also stop at an ostrich farm for Michael because "I've never seen one in real life." At the pharmacy they discover the pharmacist they spoke with before they left is not on duty. Andy wants to leave and come back "when Phil is here" but Michael insists they go ahead. The pharmacist, David, tells them Phil left clear instructions and begins to read the instructions for the process. The men want to skip that part since Phil told them about it but David tells them it's required. Next Andy tries to pay for the prescription, telling Michael "Just let me do this" even though it's really expensive but then his credit card is denied. After the pharmacy they check into a hotel which once again Andy had intended to pay for but can't since his card isn't working. In the room Andy suggests that he keep the prescription in his upstairs apartment since it is safer from floods and thieves. He then goes back to the pharmacy and purchases a children's toy safe to keep it in. Andy won't tell Michael the combination for the safe. After hanging out in the hotel room for a while they go to a bar where it is a combination of karaoke and open-mic. Andy goes to the bathroom and stares into the mirror while practicing his half-time speech. He comes out clearly prepared to tell it to Michael and maybe everyone but decides against it when he sees David, the pharmacist, has joined Michael at the bar. Andy's actions and comments make it obvious that he doesn't like David's intrusion on their time together. It is at this point that Michael steps up to the mike and starts to tell everyone about "a very special movie" that he enjoys very much ("Death Punch") and describes some of the scenes in the movie that we've seen when they watched earlier. As Michael's description begins to falter Andy comes to his rescue and together they do a good job of portraying the scenes. Later at the hotel they decide to enjoy the hot-tub even though it's after hours. They are joined by the clerk who checked them in earlier who lets them know she thinks that what they have together is wonderful. They ask for clarification and she says its obvious that the two of them have a very special, close relationship. They realize she thinks they are homosexual and they tell her they aren't. As conversation continues it becomes clear the clerk is attracted to Andy so Michael excuses himself to the room. When Andy comes back in he can't tell if Michael is breathing or not so he wakes him. Michael asks how it went with the clerk and Andy says nothing happened. The next morning Michael is gone along with the safe and Andy panics. He runs around the area trying to find Michael til he winds up back at the hotel to discover him in the lobby relaxing. Andy then grabs the safe and refuses to give it back to Michael. Next we see them driving home, not speaking to one another and Andy riding in the backseat holding the safe. Once they arrive home Andy sets the safe on the stairs and Michael comes out to pick it up. Andy gives Michael a riddle to determine the combination, Michael guesses it and they share a laugh together. Andy tells Michael that if he is acting strangely then it's because he finds it difficult to just be normal during this process. Michael nods in acknowledgement. Next there are several scenes where we see them back in their routines, spending time together but also showing Michael getting weaker and sicker. At a birthday celebration for Andy with just the two of them in Michael's apartment, Andy blows out his cupcake candle then asks Michael "You still got cancer." Michael laughs and says yeah and Andy says "That never works", ostensibly referring to his birthday wish. Some time later as they are hanging out together Michael says he's ready to take the prescription. As they prepare the concoction Andy offers to tell Michael his half-time speech. Michael tells him he's already heard it, many times, through the vent as Andy practiced it upstairs. They laugh about this. Andy then tells Michael that when Michael was applying for the apartment, Andy thought he looked like weird, "like you might be one of those guys with a lot of hands and feet in your freezer" and he tried to talk the manager into not renting to him. He says this was before he knew Michael was such a cool guy. Michael then asks about his hang-man shirt and Andy tells him that the shirt doesn't actually have an answer. When Michael asks why he would do that Andy says it's because he's noticed that when they did jigsaw puzzles together, they enjoyed the hard work and the process of completing it and even though they were happy at the end to have completed it, Michael always seemed "just a little sad" that it was over. Andy thought he would give Michael a puzzle that he could think about and work on, enjoying the process but never having that moment of sadness since he could never get it. Andy hoped that this would make it Michael's favorite shirt. Michael then takes the anti-nausea pill to keep him from throwing up after he takes the lethal prescription. While they wait an hour for it to completely kick in, they have their final conversations. Michael tells Andy he can have his car and his phone. Andy says he'll take the car but doesn't want his phone, he wants a better phone. Michael asks why he wants a better phone since he probably won't know how to use it anyway. Michael then asks Andy if he wants to arrange a signal that Andy would recognize as being from Michael just in case there is an afterlife. They banter back and forth about what would be a good sign, never settling on one, when Andy's timer goes off for the elapsed hour. Back in Michael's apartment, Michael considers different options on where he wants to be at the end before finally deciding on the bedroom. Andy goes to the kitchen to mix the drink (the lethal prescription powder mixed with water) and brings it to him. Michael pauses briefly and sets the glass down like he might be reconsidering before picking up the glass and swallowing it all quickly. Michael wants to lay down so they both stretch out together side-by-side on Michael's bed. Michael quickly starts to become very anxious, shaking and crying, telling Andy he's scared. Andy sits up and begins doing his best to calm Michael, telling him that it will be all right, everything is going to be OK. Michael asks to hold Andy's hand, tells him he's going a good job and tells him that he loves him. Andy places his other hand comfortingly on Michael's head as Michael breathes deeply to try and maintain control. Both are crying. Michael tells Andy he's going to close his eyes. Very soon Michael's breathing becomes shallow. Michael has stopped shaking and Andy tells him "I love you too" just as Michael seems to have one final exhale. Next we see Andy as he continues life without his best friend, doing things like watching "Death Punch", playing Paddleton alone. In the final scene we see a mother and young son moving into Michael's apartment. Andy helps her carry an armload of stuff to her door and tries to strike up a conversation with her son, offering to teach him Paddleton sometime ("It doesn't sound like a lotta fun, but it is".)