The availability of antiretroviral therapy has significantly reduced the morbidity and mortality of HIV infection. In addition, improved treatment of opportunistic infections and comorbidities common to patients with HIV is further prolonging the lives of patients. Improvement in the treatment of HIV has led to a significant increase in the number of medications which caregivers are able to utilise to manage HIV/AIDS. Antiretroviral medications, as well as many of the drugs used in the management of opportunistic infections and primary care (e.g., macrolide antibiotics, azole antifungals, cholesterol-lowering medications), are particularly prone to drug interactions. The interpretation of clinically significant interactions is complicated by the rate at which new information on drug metabolism and transport is becoming available. Management of drug interactions in HIV is further confounded by conflicting study results and differences between documented and theoretical inter-actions. The mechanisms and significance of interactions involving antiretrovirals, drugs used for opportunistic infections, and other medications commonly used in HIV patients will be reviewed.