The greatest challenge faced by HIV-treating clinicians today is the management of virologic failure and metabolic complications of anti-HIV treatment. Resistance testing plays an essential role in selecting appropriate agents for salvage therapy. Too often, however, the choice of agents is limited by broad cross-resistance or toxicities, such as hyperlipidemia, peripheral neuropathy, and lipodystrophy. The development of new drugs and new drug combinations offers hope for the future. Novel agents have demonstrated efficacy in treatment-experienced patients in whom current therapy is failing. Sustaining the benefits of these newer agents requires appropriate selection of other drugs in the regimen, guided by resistance testing. Many drugs retain partial activity even against resistant virus. Thus, suitable background regimens can be constructed by combining several partially active agents. No one approach can be recommended for all patients, because the pattern of drug resistance and other factors such as regimen complexity, toxicities, and disease stage must be taken into account.