The film opens to a young George Jung (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.
As an adult, George (Johnny Depp) moves to Los Angeles with his friend "Tuna" (Ethan Suplee); they meet Barbara (Franka Potente), an airline stewardess, who introduces them to Derek Foreal (Paul Reubens), a marijuana dealer. With Derek's help, George and Tuna make a lot of money. Kevin Dulli (Max Perlich), a college student back in Boston, visits them and tells them of the enormous market—and demand—for pot in Boston. With Barbara's help, 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 Santiago Sanchez (Tony Amendola), a Mexican drug lord. But two years later, George is caught in Chicago trying to import 660 pounds of marijuana and is sentenced to two years. After unsuccessfully trying to plead his innocence (by reciting the lyrics of Bob Dylan's "It Ain't Me Babe" and insisting that he did no more than "cross an imaginary line with a bunch of plants"), George skips bail to take care of Barbara, who is suffering from, and eventually succumbs to, cancer. Her death marks the disbanding of the group of friends; even his friend, Tuna, flees their vacation home in Mexico and is never seen again.
While hiding from the authorities, George visits his parents back in New England. 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 26 months in a federal prison in Danbury, Connecticut. His cellmate Diego Delgado (Jordi Molla) has contacts in the Medellín cocaine cartel and convinces George to help him go into business. Upon his release from prison, George violates his parole conditions and heads down to Cartagena, Colombia to meet up with Diego. They meet with cartel officer Cesar Rosa to negotiate the terms for smuggling 15 kilograms (33 lb) to establish "good faith". As the smuggling operation grows, Diego gets arrested, leaving George to find a way to sell 50 kg (110 lb) and get the money in time. George reconnects with Derek in California, and the two successfully sell all 50 kg in 36 hours, amassing a $1.35 million profit. George is then whisked off to Medellín, Colombia, where he finally meets the group's leader, Pablo Escobar (Cliff Curtis), who agrees to go into business with them. With the help of main middleman Derek, the pair becomes Escobar's top US importer. At Diego's wedding, George meets Cesar's fiancée Mirtha (Penélope Cruz) and marries her. However, Diego resents George for keeping Derek's identity secret and pressures George to reveal his connection. George eventually discovers that Diego has betrayed him by cutting him out of the connection with Derek. Inspired by the birth of his daughter and chastened by a subsequent drug-related heart attack, George severs his relationship with the cartel and vows to leave the drug business forever.
All goes well with George's newfound civilian life for five years, until Mirtha organizes a 38th birthday party for him. Many of his former drug associates attend, including Derek, who reveals that Diego eventually cut him out as well. The FBI and DEA raids the party and arrest George. Following George's conviction, he becomes a fugitive. Meanwhile, his bank account—heretofore under Manuel Noriega's protection in Panama—is seized. One night, he and Mirtha get into a fight while driving. They are pulled over by police and Mirtha tells them Jung is a fugitive and has stashed a kilogram of cocaine in his trunk. He is sent to jail for three years, during which time Mirtha divorces him and takes custody of their nine-year-old daughter, Kristina "Sunshine" Jung (Emma Roberts). Upon his release, George finds himself struggling to keep his relationship with his daughter on good terms.
George promises Kristina a vacation in California and seeks one last deal to garner enough money for the trip. George completes a deal with former accomplices but learns too late that the deal had been set up by the FBI and DEA, with Dulli and Derek having leaked the nature and location of the action in exchange for pardons for their involvement in his prior action. George is sentenced to 60 years at Otisville Correctional Facility in upstate New York. He explains in the end that neither the sentence nor the betrayal bothered him, but that he can never forgive himself for having to break a promise to his daughter.
While in prison, George requests a furlough to see his dying father, Fred. His unforgiving mother denies the request, saying a visit would only upset Fred. George 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 finally, too late, his understanding of what Fred meant when he said that money is not "real".
The film closes with George as an old man in prison, imagining that his daughter (Jaime King) finally comes to visit him. She slowly fades away as a guard calls for George. The film concludes with notes indicating that Jung's sentence will not expire until 2015, and that his daughter has yet to visit him. The film's final image is a photograph of the actual George Jung.

Question: Why can George never forgive himself after being sentenced to 60 years in prison?
Answer: Because he broke a promise to his daughter
Alternative answer: He had to break a promise to his daughter.