Treatment failure is still common in HIV-infected patients despite the use of multidrug antiretroviral therapy. In the absence of maximal suppression of viral replication during antiretroviral therapy, the selection for and accumulation of drug-resistant mutations is inevitable. This is reflected by a detectable viral load; in this setting, the therapy is changed in an attempt to better control viral replication. Strategies used when selecting salvage therapy include resistance testing to help guide the choice of regimen, exploiting pharmacokinetic interactions by boosting protease inhibitor trough levels, and counseling the patient on adherence. Salvage regimens should include as many new agents to which no or minimal resistance is anticipated as are available and an agent in a class that has not been previously used. The selection of salvage therapy remains complex and needs to be individualized.