After growing up watching his father, Fred (RAY LIOTTA) not get anywhere after working hard all of his life and dealing with his mother, Ermine (RACHEL GRIFFITHS), often walking out on them, George Jung (JOHNNY DEPP) and his best friend Tuna (ETHAN SUPLEE) decide to move from their Massachusetts hometown to sunny California in 1968.
There, they meet a free spirited young woman, Barbara (FRANKA POTENTE), and her friends who introduce them to the world of pot smoking. That eventually leads to them meeting Derek Foreal (PAUL REUBENS), a local dealer, when they decide to start selling pot themselves. They eventually become quite successful when another hometown friend, Kevin Dulli (MAX PERLICH), visits and tells them they could make a fortune selling to the east coast colleges. With Barbara, a stewardess, transporting the pot and Kevin dealing it back east, George and Tuna's business really takes off, especially when they start transporting the drugs directly from Mexico.
Things go great for George and his friends until he's busted in 1972. Skipping bail to care for Barbara, his now terminally ill girlfriend, George is eventually caught and sent to prison. Yet, this setback turns into opportunity when his cellmate, Diego Delgado (JORDI MOLLA), turns him onto the world of cocaine trafficking. Soon, George meets Pablo Escobar (CLIFF CURTIS), the powerful Columbian head of international cocaine trafficking, who wants George to be his dealer in the U.S., and then meets and marries Mirtha (PENELOPE CRUZ), an exotic beauty.
As the years pass, George tries to continue living his high lifestyle despite repeated run-ins with the law, being double-crossed by former acquaintances, his eventual estrangement from Mirtha and their young daughter, Kristina Sunshine Jung (EMMA ROBERTS), and his second thoughts about being in the drug business altogether.