Currently available anti-HIV drugs can be classified into three categories: nucleoside analogue reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. Knowledge of these anti-HIV drugs in various physiological or pharmacokinetic compartments is essential for design and development of drug delivery systems for the treatment of HIV infection. The input and output of anti-HIV drugs in the biological systems are described by their transport and metabolism/elimination in this review. Transport mechanisms of anti-HIV agents across various biological barriers, i.e., gastrointestinal wall, skin, mucosa, blood cerebrospinal barrier, blood-brain barrier, placenta, and cellular membranes, are discussed. Their fates during and after systemic absorption and their metabolism-related drug interactions are reviewed. Many anti-HIV drugs presently marketed in the US bear some significant drawbacks such as relatively short half-life, low bioavailability, poor penetration into the central nervous system, and undesirable side effects. Efforts have been made to design drug delivery systems for the anti-HIV agents to: (1) reduce the dosing frequency; (2) increase the bioavailability and decrease the degradation/metabolism in the gastrointestinal tract; (3) improve the CNS penetration and inhibit the CNS efflux; and (4) deliver them to target cells selectively with minimal side effects. We hope to stimulate further interests in the area of controlled delivery of anti-HIV agents by providing current status of transport and metabolism/elimination of these agents.