Substance abuse and HIV/AIDS are two of the most serious, yet treatable diseases worldwide. Global access to HIV treatment continues to expand. In settings where both active illicit drug use and HIV treatment are concurrent, potentional problematic pharmacokinetic drug interactions may arise and complicate therapy. Clinical case series and carefully controlled pharmacokinetic interaction studies have been conducted between only a few drugs of abuse and approved antiretroviral therapies. Important pharmacokinetic drug interactions have been described for benzodiazepines, 3,4-methylenedioxymethamphetamine, methadone and buprenorphine; however, most have not been studied and few well-controlled studies have been conducted to adequately address the clinical implications of these interactions. The metabolism of drugs of abuse, description of the known interactions, and clinical implications and management of these interactions are reviewed. Certain interactions between drugs of abuse and antiretroviral therapies are known and others are likely based upon shared metabolic pathways. These may result in important clinical consequences. To optimize care, clinicians must be alert, knowledgeable about known and possible interactions and equipped to clinically manage the medical consequences. Moreover, there is considerable need for carefully controlled studies in this important and emerging area.