AIDS dementia complex affects 15-20% of HIV-infected adults and a greater percentage of HIV-infected children. Whether or not an HIV-infected individual develops neurological disease and how early in infection the clinical signs appear is most likely the net result of both viral virulence factors and host factors. Important viral factors include cell tropism and sequences that determine neurovirulence. The host factors include the cellular expression of viral co-receptors and maintenance of competent immune responses. The pathogenesis of AIDS dementia complex is difficult to study in the human host because of the difficulty in identifying acutely infected individuals and the inaccessibility of human brain tissue for examination during infection. The SIV/ macaque model is excellent for the study of viral virulence factors and host responses to infection. This review outlines how the SIV/macaque model has been used to identify viral factors that are important for the development of neurological disease, to determine when HIV enters the brain, and to characterize the host immune responses affecting virus entry to the CNS and the development of neurological disease.