The pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage and administration of protease inhibitors are reviewed. Protease inhibitors are a novel class of drugs used for the treatment of human immunodeficiency virus (HIV) infection. Saquinavir, ritonavir, indinavir, and nelfinavir have been approved in the United States; several other agents are under development. Protease inhibitors selectively block HIV protease, an enzyme involved in the later stages of HIV replication. Various pharmacokinetic differences exist among these agents, including differences in bioavailability, protein binding, and drug interactions. The drugs undergo extensive hepatic metabolism; dosage adjustments should be considered for patients with hepatic dysfunction. Clinical trials have shown protease inhibitors to be effective in reducing HIV RNA levels and increasing CD4+ lymphocyte counts. When protease inhibitors are used in combination with other antiretroviral agents, an additional beneficial effect on these markers occurs. Adverse effects of saquinavir and nelfinavir include mild gastrointestinal disturbances such as diarrhea. Ritonavir is less well tolerated because of gastrointestinal disturbances and circumoral and peripheral paresthesia. Indinavir has been associated with nephrolithiasis and asymptomatic hyperbilirubinemia. The development of resistance to protease inhibitors may be related to suboptimal dosages, noncompliance, or partial compliance. Protease inhibitors are potent and highly selective agents that block a critical step in HIV replication. They are effective and relatively well tolerated, but they are expensive, have extensive drug interaction profiles, and require careful compliance with the prescribed regimen.