Richard (Leonardo DiCaprio), a young American man with a love of world travel, arrives in Bangkok, Thailand in search of adventure. At his guesthouse he briefly meets Daffy (Robert Carlyle), a mentally disturbed Scottish traveler who tells him of a pristine island in the Gulf of Thailand, uninhabited and forbidden, on which there lies a beautiful hidden beach and lagoon - walled in by cliffs and untouched by the tourist industry. He explains in vague terms that he settled there in secret with a group of others, but that difficulties arose and he chose to leave. Later, Richard finds a hand-drawn map showing the island's location left for him; he then enters Daffy's room to find him dead by suicide.
Two years after the events in the previous film, the Baker family begins to undergo many changes, beginning with Lorraine (Hilary Duff) and her desire to study in New York. Their oldest daughter Nora (Piper Perabo) is now married to Bud McNulty (Jonathan Bennett) and heavily pregnant. They intend to move to Houston because of Bud's new job promotion.
Teenage friends Will McKenzie, Simon Cooper, Jay Cartwright, and Neil Sutherland have finished their A-levels and are about to leave Rudge Park Comprehensive, much to the relief of Mr. Gilbert, their sardonic sixth form tutor. Within their final week of school, Jay's grandfather dies, Simon is dumped by his girlfriend Carli D'Amato, and Will's divorced father tells him he has married his much younger mistress. The boys decide to go on holiday together and Neil books them a trip to Malia, Crete.
Bob Munro (Robin Williams), a successful California beverage company executive, is struggling with a dysfunctional family, with his materialistic wife Jamie (Cheryl Hines), his sharp-tongued teenage daughter Cassie (JoJo), and his son Carl (Josh Hutcherson), who is an adolescent weightlifter and likes Hip hop. At a company picnic, Bob is embarrassed in front of his self-absorbed boss Todd (Will Arnett) by Cassie's militant friend Gretchen, who hurls a tub of disgusting slime over Todd. Looking forward to a big family vacation in Hawaii, their trip is cancelled when Todd, out of spite, tells Bob that he has to attend a meeting with the Alpine Soda company in Boulder, Colorado instead, or else he will be fired. Concealing the real reason for going there, he rents a garish RV from the dodgy dealer Irv (Barry Sonnenfeld) and tells his family they are traveling to the Rockies.
The characters from the first two films get together again, 27 years on, in Sardinia. The obsession with sex has not disappeared but has taken a backwards step in the face of financial preoccupations. Bernard and Nathalie Morin (Gérard Jugnot, Josiane Balasko), are the parents of a son who reveals a homosexual liaison; J.C. (Michel Blanc) and Gigi (Marie-Anne Chazel), are living together; Jérome Tarayre (Christian Clavier), is divorced and seems unhappy in his new life; Christiane Weissmuller (Dominique Lavanant), has joined an esoteric sect and wants revenge on Jérome who messed up an operation he performed on her; Popeye (Thierry Lhermitte), has become the proprietor of the hotel where the group has re-assembled, and is as unfaithful as ever.
The Heffley family attends a pool party at the local pool, where the family meets a former trouble-making friend of Rodrick (Devon Bostick) who is now a model student after attending a military school known as Spag Union, into which Greg's dad Frank (Steve Zahn) thinks about joining Greg.
With Christmas only a few weeks away, Chicago resident Clark Griswold (Chevy Chase) decides it is time to get a Christmas tree. He gathers his wife Ellen (Beverly D'Angelo), daughter Audrey (Juliette Lewis) and son Rusty (Johnny Galecki) and drives out to the country where he picks out a huge tree. Realizing too late that they didn't bring any tools to cut the tree down, they are forced to uproot it instead.
Clark Griswold (Chevy Chase), wanting to spend more time with his wife Ellen (Beverly D'Angelo) and children Rusty (Anthony Michael Hall) and Audrey (Dana Barron), decides to lead the family on a cross-country expedition from the Chicago area to the Los Angeles amusement park Walley World, billed as "America's Favorite Family Fun Park." Ellen wants to fly, but Clark insists on driving, so he can bond with his family. He has ordered a new car in preparation for the trip, but the dealer (Eugene Levy) claims that it will not be ready for six weeks. Clark is forced to accept a Wagon Queen Family Truckster, an ugly, out-sized station wagon, as the car he brought to trade in has already been hauled away and crushed.
In the Victorian period, two young cousins, Richard and Emmeline Lestrange, and a galley cook, Paddy Button (Leo McKern), survive a shipwreck in the South Pacific and reach a lush tropical island. Paddy cares for the small children and forbids them by "law" from going to the other side of the island, as he found evidence of remains of bloody human sacrifices. He also warns them against eating a scarlet berry which is apparently deadly.
The Griswold family competes in a game show called Pig in a Poke and wins an all-expenses-paid trip to Europe. In a whirlwind tour of western Europe, chaos of all sorts ensues. They stay in a fleabag London hotel with a sloppy, tattooed Cockney desk clerk (Mel Smith). While in their English rental car, a yellow Austin Maxi, Clark drives the family endlessly around the busy Lambeth Bridge Roundabout for hours, unable to maneuver his way out of traffic. His tendency to drive on the wrong side of the road causes frequent accidents, including accidentally knocking over a bicyclist (Eric Idle), who reappears throughout the film. At Stonehenge, Clark backs the car into an ancient stone monolith, toppling all the stones like dominoes, which they do not even notice as they happily leave the scene.
In the summer following their first year of college, we revisit four friends who have been apart all year and plan to spend their summer apart until a magical old pair of pants reunites them. Bridget (Blake Lively) visits her grandmother Greta (Blythe Danner) in Alabama to ask about her mother's suicidal depression. Lena (Alexis Bledel) finds her former flame Kostas (Michael Rady) married in Greece. Tibby (Amber Tamblyn) goes through a pregnancy scare and alienates Carmen. Carmen (America Ferrara) auditions for Perdita in a Vermont acting workshop. When Lena's sister Effie (Lucy Hale) steals and loses the Pants in Greece, the Sisterhood follows.
Tripper Harrison (Murray) is the head counselor of a group of new counselors-in-training (CITs) at Camp North Star, a cut-rate summer camp. Camp director Morty Melnick (Atkin) falls victim to Tripper's practical jokes mainly by being taken from his cabin in the middle of the night and being relocated to an unusual place such as in a hammock above the trees or along the roadside outside of camp.