The pandemic spread of acquired immunodeficiency syndrome (AIDS) has promoted an unprecedented scientific and clinical effort to understand and combat this lethal disease. The etiological agent of AIDS has been identified as a retrovirus of the Lentiviridae. Originally referred to as HTLV-III or LAV, this enveloped, single-stranded RNA virus is now designated human immunodeficiency virus (HIV), and two genetically distinct subtypes, HIV-1 and HIV-2, have been characterized. Infection by the virus, which targets monocytes expressing surface CD4 receptors, eventually produces profound defects in cell-mediated immunity. Over time infection leads to severe depletion of CD4+ T-lymphocytes resulting in opportunistic infections, neurologic and neoplastic disease, and ultimately death. Identification of the molecular events critical to virus replication has enabled the selection of several strategies for potential chemotherapeutic intervention. Among those, blockade of the virally encoded protease has become a major target in the quest for an effective antiviral agent.