Two years following their success in the 21 Jump Street program, Schmidt (Jonah Hill) and Jenko (Channing Tatum) are back on the streets chasing narcotics. However, after failing in the pursuit of a group of drug dealers led by Ghost (Peter Stormare), Deputy Chief Hardy (Nick Offerman) puts the duo back on the program to work for Captain Dickson (Ice Cube) – now located across the street at 22 Jump Street. Their assignment is to go undercover as college students and locate the supplier of a drug known as "WHYPHY" (Work Hard, Yes, Play Hard, Yes) that killed a student photographed buying it on campus.
Deena (Kate Bosworth) and Kim (Krysten Ritter) each bring home a guy one night. Realizing they have no condoms, they go looking around in their house where Deena ultimately finds the last one and Kim has unprotected sex. One year later, Kim is a single mother. She still lives with her two girlfriends, Deena and Laura (Rachel Bilson) while trying to juggle her son named Max. She takes Max to his father Mark (Coiro) but he announces that he is not interested in being a father. Kim brings Max along to work with her one day, as a dog service company assistant to her youth-obsessed boss Francesca (Kristen Johnston). Franchesca reprimands Kim for bringing Max with her and says that she would be fired if she does it again. Kim then takes Max to her grandfather (Seymour Cassel) who is currently living in a retirement home. Meanwhile, Deena tries to finish writing her book in a library and ends up hooking up with a guy. One night, as Kim works as a bouncer in one of Francesca's party, she falls for a guy named Nicolas (Stults) who was with two of his friends, Henri (Kirk) and Sergei (Biggs), attending the party. That night, Francesca finally allows Kim to have a break and meet up with Nicolas who promised to buy her a drink earlier and they spend the night getting to know each other. They quickly form a relationship after Nicolas intently asks Francesca to have Kim take his dog in his house. Kim brings along Max with her yet again where she lies to Nicolas that Max is a child of one of her roommates and that she was just relied on to look after Max. Kim asks Deena to come with her on her date with Nicolas that evening where Deena agrees. Nicholas arrives along with his friend Henri, where they look to Deena as her roommate with the baby. Kim begs Deena to just go with the lie they've come up with where Deena responds that it wouldn't take long enough for them to know that Kim is the one with a baby. They have a double date where it seems that Deena and Henri are attracted to each other, although Henri dresses up in hippie clothing. The next day, Deena seems promoted from her career as a writer when someone could recognize her from an article she wrote. Kim on the other hand, seems to be an underdog as Francesca wouldn't allow to invest in her own dog service business. Laura, the other roommate seems to be unstable as she has been shifting jobs every week. Kim asks her to take care of Max since she has a date with Nicholas that night, but tells her she can't. She then freaks out and calls Deena who isn't answering her calls. Finally, she asks a young boy to babysit Max for her. Nicolas and Kim have sex after their romantic date, but it's not long before Nicolas discovers Kim's secret when milk leaks out of her breasts. This leaves Nicholas upset and Kim leaves. On her way home, she sees a paramedic leave and asks Deena what happened. Kim yells at Deena for not returning home early where Deena strikes back at her saying that Max is her responsibility and there is nothing that could excuse her behavior. Deena and Kim's friendship is compromised. Kim spends all day around the house and finally quits her job telling Francesca she never looked 21. The next day, Kim informs Deena that she has to move out of the house and focus her life on being a mother and as for Deena, her successful career. Kim buys a house and visits Mark who regrets everything he said about not being ready and he wants a shot of being a dad for once. Laura then enters a show competition and seems to be successful. Kim finally reconciles with Deena and Nicolas where they all play pool together.
The Stooges are in jail when their mother sends them a letter. The letter states that their father (Curly Howard, pulling double duty as both himself and his father) has just become rich via an oil well and is planning to leave their mother and marry young gold digging blonde Daisy (Lucille Lund). The Stooges break out of jail and set off to try to stop the wedding. But since Curly and his father look exactly alike, Daisy ends up marrying the wrong man. The Stooges manage to escape the clutches of the criminals trying to kill them for their father's oil money, and rescue their father.
Farhan Qureshi (R.Madhavan) and Raju Rastogi (Sharman Joshi) are students at the Imperial College of Engineering (ICE), a highly regarded Indian engineering college. Farhan's passion is wildlife photography, but he pursues an engineering degree to appease his father. Raju chooses engineering with hopes of improving his family's financial situation, but his lack of self-confidence results in poor grades. Their third roommate and friend, Ranchodas 'Rancho' Shamaldas Chanchad (Aamir Khan), has immense interest in robotics, and invents in his spare time. Rancho regularly faces the wrath of the college's director, Dr. Viru Sahastrabuddhe (Boman Irani), known as "Virus", when he gives creative and unorthodox answers in class. He lives by the philosophy that one should pursue excellence, as when it is achieved, success follows. Virus is shown as an extremely strict person—so strict that he caused his own son's suicide by putting him under excess pressure. The star student of their class is Chatur Ramalingam (Omi Vaidya) nicknamed "Silencer", known for his incredible techniques of memorization but more notorious for his silent but malodorous flatulence in addition to his arrogant attitude. Catering for them and the other college students' needs is Man Mohan, nicknamed "Millimeter".
Andy Stitzer (Steve Carell) is a 40-year-old virgin who is involuntarily celibate. He lives alone, collects action figures, plays video games, and his social life seems to consist of watching Survivor with his elderly neighbors. He works in the stockroom at an electronics store called SmartTech. When a friend drops out of a poker game, Andy's co-workers David (Paul Rudd), Cal (Seth Rogen), and Jay (Romany Malco) reluctantly invite Andy to join them. At the game (which he wins, due to playing online poker constantly), when conversation turns to past sexual exploits, Andy desperately makes up a story, but when he compares the feel of a woman's breast to a "bag of sand", he is forced to admit his virginity.
Convicted thief Albert Ganz is working as part of a road gang in California, when a big Native American man named Billy Bear drives up in a pickup truck and asks for water to cool off his truck’s overheating radiator. Ganz and Billy exchange insults and proceed to stage a fight with each other, wrestling in a river, and when the guards try to break up the fight, Billy slips a gun to Ganz, and Billy and Ganz kill two of the three guards and flee the scene. Two days later, Ganz and Billy kill Henry Wong (John Hauk), who was one of their partners.
San Francisco cop Jack Cates is at the Hunter's Point Raceway checking out a known associate of the Iceman, Tyrone Burroughs, who for unknown reasons is giving some money to mechanic Arthur Brock.
Ten years after a covert military experiment on a remote Pacific island went wrong and killed eighteen servicemen and his assistant, Dr. Richard Long (David Paymer) is still trying to forget the havoc and death that his experiment caused.
The Stooges are mediocre paperhangers. Their client Mr. Beedle (Robert Williams) advises the boys to do a good job, but the end result looks like it was quickly cluttered with paper towels. Beedle is fuming, and threatens the boys, who make a quick escape across the hallway into the laboratory of the insane Professor Panzer (Vernon Dent) and his assistant Nikko (Frank Lackteen). Panzer is searching for a human brain puny enough to place in the head of his gorilla Igor (Art Miles). Curly becomes the prime candidate, and Panzer locks the boys in his lab in order to secure Curly's "contribution." Then Igor gets loose, but takes a liking to Curly, which the feeble-minded Stooge reciprocates. Eventually, the boys destroy Panzer's lab and quickly depart, taking Igor with them.
When the Twin Towers went down in 2001, Charlie Fineman (Sandler) lost everything important in his life. Five years have passed since Charlie's wife and daughters died, and now the once-successful and sociable man has become a withdrawn shadow of his former self.
The Stooges are once again unemployed. After an unsuccessful attempt to steal a watermelon from a deliveryman (Cy Schindell), which lands them in trouble with a cop (William Irving), the boys wind up at the offices of the Canvas Back Duck Club. The club, run by conmen Blackie (Lynton Brent) and Doyle (Wheaton Chambers) needs some salesmen and the trio have no trouble getting the job because, unbeknownst to them, the whole thing is a scam. Dressed in duck-hunting gear, Larry, Moe and Curly invade the police station and barge right into the office of the police chief (Bud Jamison). The Stooges somehow convince him, the mayor, and the entire police department to join up.
The Stooges are janitors in a doctor's office working the night shift. The usual antics occur, first with Moe getting an electrical shock down his pants, leading to a cossack dance. Then, Curly gets his head wedged inside a fish bowl, containing a live fish. Though Moe and Larry eventually slide the bowl off, Curly starts to feel the swallowed fish tickling his insides. Moe manages to fish the aquatic critter out of Curly.
Archie Moses (Adam Sandler) is a small time crook and a thief who lives in Los Angeles, and he is working for a local drug lord Frank Colton (James Caan). He is unaware that his best friend Rock Keats (Damon Wayans) is actually an LAPD undercover cop, with a real name being Jack Carter, who is seeking evidence against Colton, and he befriended Moses only to infiltrate Colton's gang.
Miles Raymond is an aspiring – but unsuccessful – writer, a wine aficionado and a divorced, depressed, borderline alcoholic middle-aged English teacher living in San Diego, who takes his soon-to-be-married actor friend and college roommate Jack Cole, on a road trip through Santa Ynez Valley wine country. Though still recognized on occasion, Jack's acting career appears to have peaked years ago, when he co-starred in a popular TV soap but now does commercial voice-overs and plans to enter his future father-in-law's successful real estate business after he's married. Miles wants to spend the week relaxing, golfing, enjoying good food and wine; however, much to Miles' consternation, Jack is on the prowl and wants one last sexual fling before settling into domestic life.