In addition to its profound effects on the immune system, HIV also infects the CNS and can cause abnormalities in infected individuals ranging from mild cognitive and motor disorders to frank dementia. We have been actively investigating the molecular and cellular mechanisms underlying the CNS manifestations of lentivirus infection through the comparative evaluation of brain pathophysiology under a number of parallel interrelated strategies. Here we describe our ongoing studies with the SIV/rhesus macaque system. We have applied an interdisciplinary multistep approach, utilizing viral, immunological, pathological, behavioral, and electrophysiological techniques to assess disease and study CNS dysfunction induced by SIV. The profile of the infection and the host response, and the resulting cognitive, motor, and neurophysiological abnormalities in SIV-infected monkeys, recapitulates many aspects of the functional impairments associated with HIV-induced CNS disease in humans. Consequently, the SIV model is ideal for examining the mechanisms underlying these functional abnormalities and for testing potential therapeutic agents.