The high incidence of neurologic dysfunction from human immunodeficiency virus (HIV) infection has heightened interest in neuropathogenesis of other lentiviruses, including that associated with feline immunodeficiency virus (FIV). Both HIV and FIV efficiently enter the central nervous system and cause primary neurological disease that is not attributable to opportunistic infections or systemic disease. Cells in the brain infected by FIV are similar to those observed in HIV infection, both viruses infect macrophages, microglia, and astrocytes. Although substantial neuronal loss can occur in the cortex of HIV- or FIV-infected patients, most studies agree that neurons are not infected and indirect mechanisms of neurotoxicity are postulated. This review describes recent information on the neuropathogenesis of FIV and how this information correlates with what is known about the neuropathogenesis of HIV. Although the pathogenesis of neurological dysfunction in HIV- and FIV-infected patients is far from clear, it is becoming increasingly evident that the relationship between lentivirus presence in the brain and neurological signs is not straightforward and cannot be explained by simple cytolytic infection. The observed neurologic dysfunction is likely multifactorial and complex involving an intricate web of subcellular pathways and neurotoxic factors interacting with multiple cell types.