Injection drug use represents the primary risk factor for up to 40% of patients with HIV infection. Physicians are generally reluctant to prescribe antiretroviral therapy (ART) for these patients due to possible poor adherence, and the potential for complex drug interactions to occur. Providing daily observed ART in conjunction with methadone maintenance therapy (MMT) has significantly improved accessibility of ART for many drug users. Knowledge of potential drug interactions between methadone, ART, and both legally and illegally prescribed drugs has permitted such interactions to be anticipated and either avoided or treated appropriately. Optimizing ART for drug users therefore demands a multidisciplinary approach from medical, clinical pharmacology and psychiatric services.