When used as initial therapy in combination with two nucleoside reverse transcriptase inhibitors, indinavir, ritonavir, nelfinavir and possible saquinavir-soft gel capsule (saquinavir-sgc) are highly effective agents. Patients who have been extensively pretreated, have advanced immunodeficiency or are unable to adhere with therapy are at high risk of failing protease inhibitor therapy. Although relevant prospective, randomized controlled clinical trails have not been reported, failure of a first protease inhibitor appears to compromise future therapeutic options. After resistance to indinavir or ritonavir emerges, salvage therapy with a protease inhibitor-containing regimen may be difficult. Preliminary data indicate that salvage therapy after resistance to saquinavir or nelfinavir emerges may be possible; however, this requires further investigation. The activity of newer agents, such as amprenavir or ABT 378, in salvage regimens is unknown. Until these issues are addressed in large prospective studies, clinicians should assume that cross-resistance will be common among all protease inhibitors.