Infection with the human immunodeficiency virus type 1 (HIV-1) remains a major potential cause of neurological disorders in children and adults throughout the world. This article provides an overview regarding the epidemiology, clinical manifestations, and neuropathogenesis of perinatally acquired HIV-1 infection. Insights regarding the mechanisms of neuroinvasion and neuropathogenesis may allow novel strategies for treating or preventing the devastating consequences of HIV-1 infection of the central nervous system (CNS).