Heavily pretreated HIV-infected patients with multidrug-resistant virus remain a clinical challenge to the treating physician. While the goal of therapy in such patients is still controversial, sustained immunologic and clinical benefit have only been demonstrated with complete suppression of plasma viral load below detectable levels. Expert use of resistance testing may help in the selection of the salvage regimen, and monitoring of plasma drug levels may help optimize the potency and tolerability, especially of complex, multiple drug regimens where adherence remains a critical determinant of treatment outcome. The potential roles of newer agents, adjuvants, treatment interruptions, and immune-based therapies remain under investigation.