Experimental and clinical evidence indicates that all lentiviruses of animals and humans are neurotropic and potentially neurovirulent. The prototypic animal lentiviruses, visna virus in sheep and caprine arthritis encephalitis virus in goats have been known for decades to induce neurologic disease. More recently, infection of the brain with the human immunodeficiency virus (HIV) has been linked to an associated encephalopathy and cognitive/motor complex. While the visna virus and caprine arthritis encephalitis virus are important models of neurologic disease they are not optimal for the study of HIV encephalitis because immune deficiency is only a minor component of the disease they induce. By contrast, the recently isolated lentiviruses from monkeys and cats, the simian and feline immunodeficiency viruses (SIV and FIV respectively), are profoundly immunosuppressive as well as neurotropic. SIV infection of the central nervous system of macaques now provides the best animal model for HIV infection of the human brain due to the close evolutionary relationship between monkeys and man, the genetic relatedness of their respective lentiviruses, and the similarities in the neuropathology. This chapter will compare and contrast the neurobiology of SIV and FIV with HIV.