Neurologic conditions associated with HIV remain major contributors to morbidity and mortality, and are increasingly recognized in the aging population on long-standing combination antiretroviral therapy (cART). Importantly, growing evidence suggests that the central nervous system (CNS) serves as a reservoir for viral replication with major implications for human immunodeficiency virus (HIV) eradication strategies. Though there has been major progress in the last decade in our understanding of the pathogenesis, burden, and impact of HIV-associated neurologic conditions, significant scientific gaps remain. In many low-income settings, second- and third-line cART regimens that carry substantial neurotoxicity remain treatment mainstays. Further, patients continue to present severely immunosuppressed with CNS opportunistic infections. Public health efforts should emphasize improvements in access and optimizing treatment of HIV-positive patients, specifically in resource-limited settings, to reduce the risk of neurologic sequelae.