The film follows a day in the life of Los Angeles Police Department officer, Jake Hoyt, who is scheduled to be evaluated by Detective Alonzo Harris, a highly decorated LAPD narcotics officer. In Alonzo's car, the officer sees teenage Mara Salvatrucha gang members dealing drugs in a park. Alonzo confiscates the drugs and tells Jake to take a hit of the marijuana. Jake refuses, but Alonzo puts a gun to his head and says that Jake's failure to use drugs could get him killed by a street dealer.
In 1996, Jamie Randall (Jake Gyllenhaal) is fired from a Pittsburgh electronics store for having sex with his manager's girlfriend. His wealthy brother Josh (Josh Gad) announces at the dinner table at their parents' (George Segal and Jill Clayburgh) house that he has found Jamie a job as a pharmaceutical sales representative. After attending a Pfizer training program where he has sex with the instructor (Kate Jennings Grant), Jamie goes to work for the company and tries to get doctors to prescribe Zoloft and Zithromax. He is rebuffed, much to the dismay of his regional manager, Bruce (Oliver Platt), who sees Jamie as his ticket to the "big leagues" of Chicago. Bruce says if Jamie can get Dr. Knight (Hank Azaria) to prescribe Zoloft instead of Prozac, other doctors will follow his lead. Jamie tries to get access to Dr. Knight by hitting on his female employees until, exasperated, Dr. Knight unethically permits him to observe him at work, during which time he accidentally sees a disrobing patient, Maggie Murdock (Anne Hathaway), who suffers from early onset Parkinson's disease.
In Pasadena, high school students Costa and J.B. plan to throw a party for their friend Thomas' birthday, aiming to increase their popularity. Thomas' parents go away for the weekend, leaving him alone in the house, but warn him not to have too many people over, and not to drive his father's Mercedes. Thomas is reluctant to have the party at his house, but Costa continues with his plan. Costa hires AV-student Dax to chronicle the night's events. Costa and J.B. advertise the party throughout the school. Thomas himself invites Alexis, the hottest girl at school, and his best friend Kirby, who has a crush on Thomas.
Dale Denton (Seth Rogen) is a 25-year-old process server and habitual pot smoker. He makes a visit to the home of his drug dealer, Saul Silver (James Franco), to buy weed. Saul tells him that he may already know the identity of Dale's next service, Ted Jones (Gary Cole). Dale drives to Ted's house and witnesses Ted and a cop, Officer Carol Brazier (Rosie Perez), shoot an Asian man to death. Dale panics and flees the area, but leaves his roach at the scene which contains a rare strain of marijuana called Pineapple Express. Ted is able to identify the strain and sends his two henchmen, Budlofsky and Matheson (Kevin Corrigan and Craig Robinson) to dealer Red (Danny McBride), who tells them that he has only sold the pot to Saul.
El Mariachi is recruited by CIA agent Sheldon Sands to kill General Emiliano Marquez, a corrupt Mexican Army officer who has been hired by Mexican drug lord Armando Barillo to assassinate the President of Mexico and overthrow the government. Many years before, El Mariachi and his wife Carolina confronted Marquez in a shootout and wounded the general; in retaliation, Marquez took the lives of Carolina and their daughter in an ambush. In addition to El Mariachi, Sands persuades former FBI agent Jorge Ramírez to come out of retirement and kill Barillo, who had murdered his partner Archuleta in the past. Furthermore, AFN operative Ajedrez is assigned by Sands to tail Barillo.
Arthur Bach (Dudley Moore) is a spoiled alcoholic from New York City who likes to be driven in his chauffeured Rolls-Royce through Central Park. Arthur is heir to a portion of his family's vast fortune, which he is told will be his only if he marries the upper class Susan Johnson (Jill Eikenberry), the daughter of a business acquaintance of his father. He does not love Susan, but his family feels she will make him finally grow up. During a shopping trip in Manhattan, accompanied by his valet Hobson (John Gielgud), Arthur witnesses a young woman, Linda Morolla (Liza Minnelli), shoplifting a necktie. He intercedes with the store security guard (Irving Metzman) on her behalf, and later asks her for a date. Despite his attraction to her, Arthur remains pressured by his family to marry Susan.
A successful New York City attorney, Gavin Banek, is in a rush to file a power of appointment, which will prove a dead man signed his foundation over to Banek's law firm. He has a collision on FDR Drive with another car, belonging to an insurance salesman, Doyle Gipson, who is also in a rush to a hearing to try to gain custody of his children and to prevent his estranged wife from taking them to Oregon. Banek tries to brush Gipson off with a blank check thereby disobeying the law. After Gipson refuses to accept the check and voices his desire to "do the right thing", that is, filing a police report and insurance claim, Banek strands Gipson, telling him, "better luck next time". After arriving to the court late, Gipson learns that it proceeded without him and that it did not go in his favor.
Billy Hope (Jake Gyllenhaal) is a boxer who lives in New York City with his wife Maureen (Rachel McAdams) and their daughter Leila (Oona Laurence). During a match in which he defends his World Light Heavyweight title, Billy sustains an eye injury and is convinced by Maureen to retire while he's at the top. At a charity event for the orphanage where he and his wife both grew up, Billy is taunted by an up-and-coming boxer, Miguel "Magic" Escobar, leading to a brawl in which Maureen is accidentally shot and killed by Miguel's brother Hector, who flees.
In a New York City park, hippies have gathered with guitars to sing protest songs. Fritz and his buddies show up in an attempt to meet girls. When a trio of attractive females walk by, Fritz and his friends exhaust themselves trying to get their attention, but find that the girls are more interested in the crow standing a few feet away. The girls attempt to flirt with the crow, making unintentionally condescending remarks about blacks, while Fritz looks on in annoyance. Suddenly, the crow rebukes the girls with a snide remark and walks away. Fritz invites the girls to "seek the truth," bringing them up to his friend's apartment, where a wild party is taking place. Since the other rooms are crowded, Fritz drags the girls into the bathroom and the four of them have group sex in the bathtub. Meanwhile, the police (portrayed as pigs) arrive to raid the party. As the two officers walk up the stairs, one of the partygoers finds Fritz and the girls in the bath tub. Several others jump in, pushing Fritz to the side where he takes solace in marijuana. The two officers break into the apartment, but find that it is empty because everyone has moved into the bathroom. Fritz takes refuge in the toilet when one of the pigs enters the bathroom and begins to beat up the partygoers. As the pig becomes exhausted, a very stoned Fritz jumps out, grabs the pig's gun, and shoots the toilet, causing the water main to break and flooding everybody out of the apartment. The pigs chase Fritz down the street into a synagogue. Fritz manages to escape when the congregation gets up to celebrate the United States' decision to send more weapons into Israel.
Detective Seo Do-cheol is tough and merciless when it comes to crime. After busting an attempt at illegal car exporting, Seo thanks a truck driver that helps Seo and his team in the operation, and gives the truck driver some money and a business card to contact him when faced with trouble.
In 1995, schemer Daniel Lugo (Mark Wahlberg) is a recently released convict who had served time for Medicare fraud. Sun Gym owner John Mese (Rob Corddry) hires him to increase membership and make the gym more fitness-based. Lugo increases the gym's membership by 75% within six weeks and befriends trainer Adrian Doorbal (Anthony Mackie), a bodybuilder who uses steroids, which render him impotent. Lugo soon lusts after the earnings and lifestyle achieved by Victor Kershaw (Tony Shalhoub), a sleazy, new gym member he begins to train who Lugo believes is a crook. Inspired by motivational speaker Johnny Wu (Ken Jeong), Lugo decides to be a "do-er" and hatches a plan to extort Kershaw for his assets by kidnapping and torturing him.
During a kidnapping raid in Chandler, Arizona, idealistic FBI Special Weapons and Tactics Teams agent Kate Macer (Emily Blunt), her partner Reggie Wayne (Daniel Kaluuya), and the rest of her team discover dozens of corpses within the walls of a house along with an improvised explosive device in the backyard shed, which kills two officers. Her boss, Dave Jennings (Victor Garber), recommends her to Matt Graver (Josh Brolin), a CIA Special Activities Division officer undercover as a supposed United States Department of Defense adviser leading a team of SFOD-D operators who are searching for the men responsible, one of them being cartel boss Manuel Díaz (Bernardo P. Saracino). Kate agrees to volunteer, eager to finally make a difference.
The film opens to a young George (Jesse James) and his parents Fred (Ray Liotta) and Ermine (Rachel Griffiths) of Weymouth, Massachusetts. When George is ten years old, Fred files for bankruptcy and loses everything, but tries to make George realize that money is not important.
Best friends Chon (Taylor Kitsch) and Ben (Aaron Taylor-Johnson) are marijuana growers living in Laguna Beach, California. Chon, a former Navy SEAL, smuggled the seeds for the plants out of Afghanistan. They got help in cultivating them from Ben, a graduate of University of California, Berkeley in business and botany. These seeds yielded a particularly potent strain of marijuana that soon developed a wide customer base and made Chon and Ben very wealthy, and Ben began devoting time and money to doing charity work in Africa and Asia. They are both in a relationship with Ophelia Sage (Blake Lively).
Esther Hoffman, an aspiring singer/songwriter, meets John Norman Howard, a famous, successful and self-destructive singer/songwriter rock star, whom, after a series of coincidental meetings, she finally starts dating. Believing in her talent, John gives her a helping hand and her career begins to eclipse his.