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Drug interactions are a leading cause of morbidity and mortality. Methadone and buprenorphine are frequently prescribed for the treatment of opioid addiction. Patients needing treatment with these medications often have co-occurring medical and mental illnesses that require medication treatment. The abuse of illicit substances is also common in opioid-addicted individuals. These clinical realities place patients being treated with methadone and buprenorphine at risk for potentially toxic drug interactions. A substantial literature has accumulated on drug interactions between either methadone or buprenorphine with other medications when ingested concomitantly by humans. This review summarizes current literature in this area. (Am J Addict 2009;19:4–16)