Patients infected with human immunodeficiency virus (HIV) develop immunologic dysfunction and multiorgan inflammatory diseases directly associated with HIV-1 infection. Of these inflammatory diseases, the most devastating to the HIV-infected patient is involvement of the central nervous system (CNS). The pathogenesis of the clinical syndrome observed in these patients, termed HIV-associated dementia, remains poorly understood. However, as most of the detectable virus in the CNS is in cells of monocyte/macrophage lineage, it is clear that penetration of the blood-brain barrier by HIV-1 and the subsequent influx of monocytes into the brain are crucial components in the neuropathogenesis of HIV-associated dementia. Using the SIV-infected macaque model of acquired immunodeficiency disease, much has been learned about viral neuroinvasion occurring soon after experimental infection. The aim of this review is to discuss these recent advances and provide insight into plausible mechanisms for monocyte entry into the CNS.