The film opens to a young George (Jesse James) and his parents Fred (Ray Liotta) and Ermine (Rachel Griffiths). Fred files for bankruptcy and loses everything. Fred tries to instill George with a belief that money is not important.
A grown-up George (Johnny Depp) moves to Southern California with his friend "Tuna" (Ethan Suplee) and they plan to earn a living by selling marijuana with the help of an airline stewardess, Barbara Buckley (Franka Potente), and a girlfriend of George who introduces them to her friend/entrepreneur Derek Foreal (Paul Reubens), the main dealer, who also runs a hair salon. With Derek's help, George and Tuna make a lot of money. Kevin Dulli (Max Perlich), a college student back in Boston who is a friend, visits them and tells them of the enormous demand for pot in Boston. With the help of Barbara, they start bringing the drugs to Boston.
As the demand grows, they decide to start buying the drugs directly from Mexico with the help of a few Mexican drug lords. George then proceeds on to Chicago to do business, but is caught trying to import 660 pounds of marijuana and he is sentenced to two years. George skips bail (after trying to plead his innocence by reciting It Ain't Me Babe) to take care of Barbara, who is suffering from, and eventually succumbs to, cancer.
While hiding from the authorities George visits his parents back in Massachusetts. While he is having a heart to heart talk with his father, George's mother calls the police who come and arrest him.
George is now sentenced to twenty-six months in a federal prison in Danbury, Connecticut. His cellmate Diego Delgado (Jordi Molla) has contacts in the cocaine trade in Colombia and convinces George to help him go into business. When George gets out of prison, he violates his parole conditions and heads down to Cartagena, Colombia to meet up with Diego. They meet with Cesar Rosa, to negotiate the terms for smuggling 15 kilograms for "good faith". As the smuggling operation grows, Diego gets arrested, leaving George to find a way to sell 50 kilos (110 lbs) of blow and get the money in time. He reconnects with Derek in California, and the two successfully sell all of it in 36 hours, amassing a $1.35 million profit. George is then whisked off to Medellin, Colombia, where he finally meets Pablo Escobar (Cliff Curtis) who agrees to go into business with George and Diego. With the help of main middleman Derek, the pair becomes Pablo's #1 importer. After an altercation with Diego over his "connection", who happened to be Derek (Diego pressured George to reveal his connection), and a drug-related collapse, George returns home and vows to leave the drug business forevermore, especially as he now has a daughter.
All goes well with George's civilian lifestyle for five years, until his wife Mirtha (Penelope Cruz) organizes a 38th birthday party for him. Many of his former drug business associates attend, including Derek who reconciles with George after it is revealed that Diego cut him off of their deal. The party is raided by police and George is arrested. Following his conviction, he becomes a fugitive dodging his court date. Meanwhile, his large Panamanian bank accounts have been seized. His wife Mirtha causes him to be arrested while driving one night. He is sent to jail for three years and during that sentence Mirtha gives him the news that she wants a divorce and she wants custody of their nine year old daughter, Kristina Sunshine Jung. On his release he finds himself struggling to keep a relationship with his daughter on good terms.
George promises his daughter Kristina (Emma Roberts) a vacation in California and goes into one last deal to garner enough money for the trip. On the deal, he is set up by the FBI and DEA, along with old accomplices, and sentenced to 60 years at Otisville Correctional Facility in upstate New York. He explains in the end that the sentence did not bother him, nor did the fact that he was betrayed by his accomplices "to save their own asses" bother him. What bothered him was he broke a promise to his daughter, in addition to the emotional damage he caused on those he loved (especially his daughter) and how his ambition exceeded his talent.
In prison, his lawyer says that his request for a furlough for George to see his dying father was squashed by his unforgiving mother, who says it would only upset him. He is given a tape recorder to record a final message to his father. In the message, George recounts his memories of working with his father, his run-ins with the law, and how finally, too late, does he realize what his father meant when his said that money is not "real".
The film closes with George being an old man in prison, imagining that his daughter finally comes to visit him and conversing with him. She slowly fades away as a guard calls for George indicating that she is not real and just an illusion. The film concludes with notes indicating that Jung is still in prison, his sentence not to expire until 2015, and his daughter yet to visit him, with the final imagery being a photograph of the actual George Jung.