Human immunodeficiency virus (HIV) protease inhibitors have revolutionized the treatment of individuals infected with this pathogen. The protease is an enzyme that is essential for viral replication because it cleaves both structural and functional proteins from precursor viral polyprotein strands. Inhibition of this process suppresses viral replication, which produces immature noninfectious virions. When combined with reverse transcriptase inhibitors, these agents are very potent in suppressing viral replication. Pharmacologic properties, toxic profile, drug interactions, and resistance patterns differ among protease inhibitors, and all must be considered when selecting the drugs for therapeutic use in humans. The best combination, sequence of use, durability of response, and magnitude of immune reconstitution and function are issues that have yet to be fully elucidated.