Laura Burney (Julia Roberts) lives in a beautiful home by the beach on Cape Cod with her husband, Martin Burney (Patrick Bergin), a charming, handsome and wealthy investment counselor who is also possessive, abusive, and controlling. It becomes apparent that he has obsessive-compulsive personality disorder (OCPD). Laura tries to abide his rules, but suffers under the strain of doing so. One day, Martin believes Laura has been flirting with an attractive neighbor, and he physically assaults her in a jealous rage. The abuse has been ongoing, and started immediately after their wedding. In an effort to escape Martin, Laura plans and fakes her own death at sea in a storm while the couple are boating. Because Laura had deliberately led Martin to believe that she could not swim, he believed she had died once she was lost overboard. However, Laura was able to swim safely to shore, because she had recently taken swimming lessons at the YWCA. Laura secretly returns home, retrieves some clothing and cash she had hidden away in preparation, disguises herself, and leaves home after flushing her wedding ring down the toilet.
Dave (Vince Vaughn), a dealer for Guitar Hero, and Ronnie (Malin Åkerman), a stay-at-home mom, are a typical couple with two young children. They experience various stresses including redecorating their house and raising their kids. Joey (Jon Favreau) and Lucy (Kristin Davis) are high school sweethearts with a smart but naive teenage daughter named Lacey. Their relationship is on the rocks. Jason (Jason Bateman) and Cynthia (Kristen Bell) are a neurotic couple who've experienced multiple failed attempts to conceive, and Shane (Faizon Love), who has recently separated from his wife, has a much younger twenty-year-old girlfriend, Trudy (Kali Hawk).
Seth (Jonah Hill) and Evan (Michael Cera) are two high school seniors who lament their virginity and poor social standing. Best friends since childhood, the two are about to go off to different colleges, as Seth didn't get accepted into Dartmouth like Evan. After Seth is paired with Jules (Emma Stone) during Home-Ec class, she invites him to a party at her house later that night. Later, Fogell (Christopher Charles Mintz-Plasse) comes up to the two and reveals his plans to obtain a fake ID during lunch. Seth uses this to his advantage and promises to bring alcohol to Jules' party. Fogell's fake ID is met with derision by Seth and Evan, as it states that Fogell's name is simply "McLovin". After contemplating their options, Seth decides they have no choice but to have Fogell buy the alcohol with his fake ID. Fogell goes in and successfully buys the alcohol, but is interrupted when a robber enters the store, punches him in the face, and takes money from the cash register.
Mike (Tatum) has big plans for a business of his own but pays his bills through a series of odd jobs, most notably performing as the star stripper at Xquisite Strip Club in Tampa, a club owned by Dallas (McConaughey), who has dreams of creating an "empire" of strip clubs.
Dr. Bill Harford (Tom Cruise) and his wife, Alice (Nicole Kidman), are a young couple living in New York. They go to a Christmas party thrown by a wealthy patient, Victor Ziegler (Sydney Pollack). Bill meets an old friend from medical school, Nick Nightingale (Todd Field), who now plays piano professionally. While a Hungarian man named Sandor Szavost (Sky du Mont) tries to pick up Alice, two young models try to take Bill off for a tryst. He is interrupted by a call from his host upstairs, who had been having sex with Mandy (Julienne Davis), a young woman who has overdosed on a speedball. Mandy recovers with Bill's aid.
The film is set in 1880 in Big Whiskey, Wyoming, where Little Bill Daggett, the local sheriff and former gunfighter, does not allow guns or criminals in his town. Two cowboys, Quick Mike and "Davey-Boy" Bunting, disfigure prostitute Delilah Fitzgerald after she laughs at the small size of Quick Mike's penis. Instead of punishing the cowboys, Little Bill allows them to pay compensation to the brothel owner, Skinny Dubois. The rest of the prostitutes, led by Strawberry Alice, are infuriated by this leniency and offer a $1,000 reward to whoever can kill the cowboys.
Artist Jennifer Spencer and her sister are raped by a group of boys, after being betrayed by female friend Ray Parkins. The brutal rape leaves Jennifer's sister permanently catatonic. Ten years later, Spencer seeks revenge. She kills one of the rapists (George Wilburn) with two shots—one in the groin and one in the head—from a .38 snubnosed revolver. Spencer then leaves San Francisco because of the subsequent police investigation. Once relocated in the town of San Paulo, Spencer begins restoring its boardwalk's historic carousel near the beach where the rapes occurred.
Jamie Rellis (Mila Kunis) is an executive recruiter for a leading job agency in New York City, and Dylan Harper (Justin Timberlake) works as an art director for a small internet company in Los Angeles. Jamie has the task of trying to recruit Dylan to interview for a job with GQ and begin working in New York City. Dylan comes to New York and after interviewing for the position learns from Jamie that he has been given an offer to work for GQ. At first Dylan is hesitant to accept the job and move from Los Angeles to New York. But after a fun night exploring the city with Jamie, Dylan agrees to accept the position.
In 1962, college freshmen Lawrence "Larry" Kroger and Kent Dorfman seek to join a fraternity at Faber College. Finding themselves out of place at the prestigious Omega Theta Pi House's party, and rejected by other houses, they finally visit the slovenly and riotous Delta Tau Chi House, where Kent's brother was once a member, making Kent a "legacy", unable to be declined. Larry and Kent are invited to pledge and given the fraternity names "Pinto" and "Flounder," respectively, by John "Bluto" Blutarsky.
Film publicist Lee Phillips (Billy Crystal) is tasked with promoting a film featuring movie stars Gwen Harrison (Catherine Zeta-Jones) and Eddie Thomas (John Cusack). His job is complicated by the fact that the eccentric director of the film, Hal Weidmann (Christopher Walken), refuses to show him a cut of the film and demands the first viewing take place at a press junket. To promote the film, Lee decides to focus on the two stars: Gwen and Eddie, once known as "America's Sweethearts". Unfortunately, they are now going through an ugly split. As a result of Gwen's affair with Hector (Hank Azaria), Eddie has an emotional breakdown and is at a New Age retreat. Lee decides that his best chance to promote the film is to reunite the couple.
Andy (Preston Jones) is egged on by his best friends to stop worrying so much about his girlfriend, Katy Hartman (Julianna Guill), back-home and start enjoying college life to the fullest. While enjoying his life, he remembers Jenna, an old girlfriend from home who is now a beer pong model and becomes infatuated with her. Andy and his friends decide to hit the road chasing Jenna and her model friends to compete in a beer pong tournament, but their plans get complicated when Katy decides to transfer to his university so she can be closer to him. They call on a son of a rich despot, Arash (Danny Pudi), who hopes to get him to sponsor their road trip but instead are taken into custody by the CIA, who interrogate them and dump them in Bethesda. They steal a taxi and continue their journey, but make a pit stop in family run strip clip, only to run afoul of a gang of bikers. Short of cash, they pick up a hitchhiker hoping she will pay for a ride. Instead, she holds up a convenience store and steals the taxi.
Jay Baruchel arrives in Los Angeles to visit with old friend and fellow actor Seth Rogen, who invites him to attend a housewarming party hosted by James Franco. Jay is uncomfortable being around so many people he hardly knows, so Seth accompanies him to a convenience store for cigarettes.
A group of Florida high school students plan on losing their virginity. They go to Porky's, a nightclub out in the Everglades, believing that they can hire a prostitute to satisfy their sexual desires. Porky takes their money but humiliates the kids by dumping them in the swamp. When the group demand their money back, the sheriff, who turns out to be Porky's brother, arrives to drive them away, but not before his minions extort the rest of their money and cause them more embarrassment. After Mickey (who returned to Porky's for revenge) is beaten so badly he has to be hospitalized, the gang becomes hellbent on exacting revenge on Porky and his brother, eventually succeeding in sinking his establishment in the swamp. Porky and his men, joined by the sheriff, chase after the group, but they make it across the county line (out of Porky's brother's jurisdiction), where they are met by a group of the local police officers, one of whom is Mickey's older brother Ted, and the high school band. After Ted repeatedly damages Porky's car, he says that all charges against Porky for driving an unsafe vehicle will be dropped if the night's events are forgiven. Because the boys were too young to be legally allowed in Porky's in the first place, Porky and his brother have no choice but to agree. The film ends with the group getting their revenge and Pee Wee finally losing his virginity.
Edward (Richard Gere) and Connie Sumner (Diane Lane) are a married couple living in a suburban New York City with their eight-year-old son, Charlie (Erik Per Sullivan). Their relationship is loving but lacking intimacy due to their schedules.