Twenty years after his disappearance in 1908, an aged Butch Cassidy (Sam Shepard), living under the assumed name James Blackthorn in a secluded village in Bolivia, decides to end his long exile and return to the United States after learning of the death of Etta Place. He writes to her son, Ryan, who is in fact his own son, telling him he intends to return. After years of raising horses and living a solitary life, Blackthorn sets off for Potosí to sell his horses. He tells his lover, Yana (Magaly Solier), that he will see her again before leaving Bolivia.
Before the dawn of man or beast, immortals waged war against each other in Heaven. The victors declared themselves gods while the vanquished were renamed the Titans and imprisoned beneath Mount Tartarus. The Epirus Bow, a weapon of immense power, was lost on Earth during the war. In 1228 B.C., the mortal king Hyperion (Mickey Rourke) of Heraklion searches for the bow, intending to use it to release the Titans to get revenge on the gods for failing to save his family. Hyperion captures the virgin oracle Phaedra (Freida Pinto), believing that she can use her visions to find the Epirus Bow's resting place.
Eddie Morra (Bradley Cooper), a struggling author suffering from writer's block, living in New York, is stressed by an approaching deadline. His girlfriend Lindy (Abbie Cornish), frustrated with his lack of progress and financial dependence, breaks up with him. Later, Eddie happens to run into Vernon (Johnny Whitworth), the estranged brother of Eddie's ex-wife, Melissa (Anna Friel). Vernon, involved with a pharmaceutical company, gives Eddie a sample of a new "smart drug", NZT-48. After taking the pill, Eddie finds himself able to learn and analyze at a superhuman rate and recall memories from his distant past, with the only apparent side effect being a change in the color of Eddie's irises while on the drug—his eyes becoming an intense shade of electric blue. Under the influence, he cleans his messy apartment and writes ninety pages of his book. The next day, the effects having worn off, he seeks out Vernon in an attempt to get more. While Eddie is out running an errand, Vernon is murdered. Eddie returns, calls the police and then discovers Vernon's NZT stash just before they arrive, taking it for himself. After giving a statement at the precinct, Eddie returns home and begins ingesting the drug daily. With the help of the drug's amazing effects, Eddie spends a few weeks cleaning up his life—finishing his book, getting fit, and making friends with a group of young jet-setters, who take him on vacation to Europe, where he mingles with the rich. During all this, Eddie tests out his enhanced learning abilities; he becomes a proficient piano player in just three days, as well as becoming fluent in several languages.
The film is set in 1988 Los Angeles. Matt Franklin (Topher Grace) is a recent MIT graduate who works at a Suncoast Video store while trying to figure out what he wants to do with his life, something that his police officer father (Michael Biehn) has grown impatient with. While working one day, Matt's high school crush, Tori Frederking (Teresa Palmer), randomly walks into the store. After pretending that he doesn't work there and saying that he works at Goldman Sachs in an effort to impress her, Tori invites Matt to a Labor Day party, hosted by Matt's twin sister Wendy's (Anna Faris) boyfriend, Kyle Masterson (Chris Pratt), at his hillside home.
Jarrod and his girlfriend Elaine have flown to Los Angeles for Jarrod's best friend Terry's birthday party. They celebrate with Terry's wife, Candice, and his assistant, Denise. During the party, one of Terry's employees, Ray, welcomes Jarrod to L.A., thinking he has moved there to join Terry's special effects company. During a private argument about whether or not they should move, Elaine reveals she is pregnant.
Young photographer Yaniv "Nev" Schulman lives with his brother Ariel in New York City. Abby Pierce, an 8-year-old child prodigy artist in rural Ishpeming, Michigan, sends Nev a painting of one of his photos. They become Facebook friends, which broadens to include Abby's family: including her mother, Angela (Wesselman); Angela's husband Vince (she uses a photo of Stephen Fogarty); and Abby's attractive older half-sister Megan, who lives in Gladstone, Michigan.
In eastern Siberia's Dzhugdzhur Mountains, Dieter Von Cunth and his men take control of the X-5 missile, which is a nuclear warhead. On the other side of the world Col. Jim Faith and Lt. Dixon Piper are searching for former Green Beret, Navy SEAL and Army Ranger MacGruber in Ecuador. The two men find MacGruber meditating in a chapel, and try to convince him to return to the United States in an effort to retrieve the warhead. MacGruber refuses; later that night, MacGruber explodes into a fit of rage after a flashback where Cunth killed his fiancée, Casey Fitzpatrick, at their wedding; he then accepts the Colonel's offer.
In 2008, an unknown killer virus, dubbed "The Reaper Virus" infects Scotland. The UK government cannot contain or cure the virus, and they decide to build a 60-foot containment wall over the border with Scotland and its islands, isolating it from the rest of Britain.
Erik Stifler and Mike "Cooze" Coozeman arrive at the University of Michigan as freshmen. Upon arriving at his dorm, Erik meets a girl named Ashley while she is taking a shower in the coed bathrooms. He then meets his new roommate Bobby and his girlfriend Margie while they are having sex. Erik eventually reunites with his cousin, Dwight Stifler, the leader of the Beta House fraternity, who invites Erik, Cooze, and Bobby to a Beta House party. They learn how they can gain eligibility to pledge for the Beta House and meet Wesley, the rush chair of the Beta House who experiences blackouts after drinking alcohol. Erik and Ashley begin dating, but on their first date at a restaurant, Erik accidentally spills hot soup on his legs, so Ashley brings him to her room to clean up. As Ashley rubs lotion on Erik's thigh, he develops an erection and accidentally ejaculates over her possessions. Erik apologizes and explains to Ashley that his girlfriend Tracy broke up with him, and he has not had sex in four months.
Matt Stifler, the younger brother of Steve Stifler, is eager to enter the family business of making porn films so he can prove himself to his older brother. After Matt plays a prank on the school band, the school's guidance counselor Chuck "The Sherminator" Sherman, who attended high school with Steve, decides that a worthwhile punishment would be for Matt to attend band camp. Matt is initially disgruntled by the idea but soon agrees to it, interested in the notorious sexual behavior of band camp girls (citing Jim's marriage and sex life with Michelle as an example).
Owen Matthews arrives at Westlake Preparatory Academy. That night Owen's roommate, Tom, tells him they are sneaking out. A group of students consisting of Graham, Mercedes, Lewis, Randall, Regina, Tom, Dodger and Owen play a game called Cry Wolf, where someone is marked as a "wolf" and the group tries to figure out who it is.
In the woods outside of Cherry Falls, Virginia, a teenage couple, Rod Harper (Jesse Bradford) and Stacy Twelfmann (Bre Blair) are getting romantic in a car when a black-haired female appears and murders them both. Meanwhile, in town, teenager Jody Marken (Brittany Murphy), the daughter of the local sheriff, is with her boyfriend, Kenny (Gabriel Mann), who thinks it is time to go "see other people." Jody goes back home to find her father, Brent (Michael Biehn), upset that she is out past her curfew. Brent and his deputies begin to investigate the murders the next day. They see that the killer carved the word "virgin" into both victims. At school, Brent sees English teacher Mr. Marliston (Jay Mohr), who urges him to divulge more details of the murder to students and the town so as to eliminate the possibility of secrets.
After serving twelve years for murder (for killing a rapist and murderer he caught in the act), Chris (Clive Owen) is released from prison in 1974. His ex-wife, Monica (Marion Cotillard), is a drug-addicted prostitute. She has a son and a daughter. Chris tries to go straight with his new girlfriend Natalie (Mila Kunis) but is betrayed and sabotaged in his pursuit of a legitimate business venture. Returning to his criminal ways puts him in direct conflict with his brother Frank (Billy Crudup) who happens to be a New York City cop. Their sister, Marie (Lili Taylor), and their sick father, Leon (James Caan), want Chris and Frank to just get along with each other.
Grace (Eva Mendes) is a single mom raising her fourteen-year-old daughter, Ansiedad (Cierra Ramirez). Grace is busy juggling work, bills, and her relationship with the very married Dr. Hartford (Matthew Modine), leaving Ansiedad to take care of herself as well as her mother most of the time.