It is clear that optimal control of HIV infection using cocktails of antiretrovirals has an important beneficial effect on the neurologic manifestations of HIV. Research is required to define the pathophysiology of HIV-associated disease in the central nervous system, and to enhance delivery of therapy to this important compartment. Concurrently, trials of potentially neuroprotective agents are needed to optimize central nervous system therapy. No neuroprotective treatment to date has been successfully proven to be beneficial. However, progress has been very rewarding, with rapidly declining incidence of neurologic disease associated with dramatic improvement in HIV therapy. The prolonged life span of patients with HIV leaves the possibility that prevalence of HIV-associated neurologic disease might even increase in coming years. Therapy for HIV in the central nervous system compartment remains potentially the most challenging therapeutic frontier for HIV control.