Research on the pathogenesis of the human immunodeficiency virus (HIV) infection of the central nervous system (CNS) has reached a pivotal stage. While the incidence of HIV dementia appears to be declining, the prevalence of milder, yet debilitating, neuropsychological impairments may rise as individuals infected with HIV live longer. There are also concerns about CNS reservoirs of latently infected cells. Building upon progress in understanding HIV neuropathogenesis, the time is ideal to expand research on the interrelationships between the CNS and systemic HIV disease, and extend the boundaries of this research to the neuropathogenic similarities between HIV and other CNS inflammatory diseases. Neuropathogenic insights gained from these pursuits can spawn new treatment strategies for HIV/CNS disease as well as potentially other diseases of the nervous system.