As one of the largest growing classes of antiretroviral drugs, protease inhibitors are promising agents for the management of patients infected with the human immunodeficiency virus (HIV). We reviewed the literature and compared efficacy, dosing, side effects, and drug-interaction profiles of the protease inhibitors saquinavir, ritonavir, indinavir, and nelfinavir. We addressed the use of these antiprotease agents as monotherapy versus use in combination therapy with other antiretroviral medications, and the potential for HIV to develop resistance to this drug class. We also discussed therapy with dual protease inhibitors and the use of protease inhibitors in pregnant or lactating women and in pediatric patients. Finally, we examined case reports of the addition of protease inhibitors to an antiretroviral regimen that ultimately decreases or reverses opportunistic infections.