The retroviral protease (PR) is responsible for cleaving precursor proteins that contain the virion structural proteins and enzymes. Highly potent inhibitors of the human immunodeficiency virus type-1 PR have been developed, and to date, five of these inhibitors have been approved for clinical use. These inhibitors bind to the active site of the dimeric PR and represent transition state analogs. Combination therapy in which a potent protease inhibitor is combined with inhibitors of the viral DNA polymerase reverse transcriptase can result in the apparent complete suppression of virus replication. Low virus loads associated with suppressed replication are resulting in dramatic reductions in the rate of disease progression. However, incomplete suppression of virus replication results in the selection of resistant variants. Resistance to protease inhibitors is the result of mutations within the PR coding domain, and most of these mutations are able to contribute to cross-resistance among this class of inhibitors.