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Mewes grew up in Highlands, New Jersey, living with his mother, a heroin addict who died of AIDS in 2002. He has never met his father. He was raised primarily by his aunt but would often steal from her so that his mother could buy drugs. He himself started using heroin in his early 20s, and remained addicted for the next decade. Smith entered Mewes into the first of a series of drug rehabilitation clinics in 1997, after noticing Mewes was nodding off during the filming of Chasing Amy. Mewes' attempt at sobriety was short-lived, however; in 1999, he was arrested for possession of heroin and a syringe, in violation of his probation. He also stole Smith's ATM card and charged $1,100 and had heroin FedExed to the hotel where the press junket for Jay and Silent Bob Strike Back was being held. Smith had taken Mewes in to live with him and his wife, Jennifer Schwalbach Smith, but kicked him out after he was caught using again. In another attempt to get clean, Mewes moved in with his mother, who gave him OxyContin to ease the withdrawal symptoms; Mewes was soon addicted to that substance as well. In 2003, he made another attempt at sobriety, this time successful; to date, he has remained sober.
While he is mostly known for acting in films, Mewes also has worked in television. He voiced the role of Jay in the short-lived Clerks: The Animated Series. He, along with Smith, appeared in the films Scream 3, Bottoms Up and Degrassi: The Next Generation. He appeared in two episodes of a three-part story arc in which he and Smith film a new addition to Smith's View Askewniverse entitled Jay and Silent Bob Go Canadian, Eh! at Degrassi Community School. They appear again on Degrassi (in a two part episode), at the the flm in Canada. Mewes, Smith, and Degrassi star Stacie Mistysyn made the cover of Canadian TV Guide. He and Kevin Smith will return to Degrassi: The Next Generation for some of the final 4 episodes of season 8 entitled Paradise City. In 1998, he starred as "Gary Lamb - Ground Activist" in a series of Nike commercials directed by Smith.
In Scarface: The World Is Yours, Mewes provides a voiceover for a thief who steals some tapes. The character's dialogue, consisting mainly of constant stream-of-consciousness profanity, is entirely consistent with that of the Jay character. Mewes starred in the pilot episode of a Kevin Smith directed sitcom called Hating Hal (which never advanced beyond the pilot stage.)
During a radio interview on WJFK 106.7, Mewes confirmed that at one time, he made a deal with Kevin Smith that if he stayed sober, they would make Clerks II. He also stated that he is doing a film called K-11 with Kristen Stewart and Nikki Reed and that he dyed his hair black for this role.