Early in the HIV epidemic, the central nervous system (CNS) was recognized as a target of infection and injury in the advanced stages of disease. Though the most severe forms of HIV-associated neurocognitive disorder (HAND) related to severe immunosuppression are rare in the current era of widespread combination antiretroviral therapy (cART), evidence now supports pathological involvement of the CNS throughout the course of infection. Recent work suggests that the stage for HIV neuropathogenesis may be set with initial viral entry into the CNS, followed by initiation of pathogenetic processes including neuroinflammation and neurotoxicity, and establishment of local, compartmentalized HIV replication that may reflect a tissue reservoir for HIV. Key questions still exist as to when HIV establishes local infection in the CNS, which CNS cells are the primary targets of HIV, and what mechanistic processes underlie the injury to neurons that produce clinical symptoms of HAND. Advances in these areas will provide opportunities for improved treatment of patients with established HAND, prevention of neurological disease in those with early stage infection, and understanding of HIV tissue reservoirs that will aid efforts at HIV eradication.