Highly active antiretroviral therapy, involving treatment with three or four antiretroviral agents, has greatly improved the effectiveness of therapy for human immunodeficiency virus (HIV) infection. It has also extended the number of possible drug interactions that may occur in treated patients. There are 105 possible two-drug interactions among the 15 currently approved antiretroviral agents. Well-characterized interactions involving inhibition of drug metabolism have been exploited to reduce dose size or frequency and to simplify treatment regimens. Many additional interactions are possible with other drugs used to treat or prevent complications of HIV infection. Interactions with methadone and other opiate abuse therapies are also of concern. The usefulness of therapeutic drug monitoring for antiretroviral drugs remains controversial. However, drug measurements before introduction of an interacting drug can establish patient-specific targets that can guide subsequent dosing adjustment.