Over the past decade there has been a revolution in the understanding and care of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)-associated disease. Much of this progress stems from a broader recognition of the importance of differences in viral types, including receptor preference(s), replication properties, and reservoirs, as contributing factors to immunosuppresion and disease progression. In contrast, there is limited conceptualizatin of viral diversity and turnover in the brain and circulation in relation to neurocognitive impairments. Herein, the authors review current concepts regarding viral molecular diversity and phenotypes together with features of HIV-1 neuroinvasion, neurotropism, neurovirulence and neurosusceptiblity. Viral genetic and antigenic diversity is reduced within the brain compared to blood or other systemic organs within individuals. Conversely, viral molecular heterogeneity is greater in patients with HIV-associated dementia compared to nondemented patients, depending on the viral gene examined. Individual viral proteins exert multiple neuropathogenic effects, although the neurological consequences of different viral polymorphisms remain uncertain. Nonetheless, host genetic polymorphisms clearly influence neurological disease outcomes and likely dictate both acquired and innate immune responses, which in turn shape viral evolution within the host. Emerging issues include widespread antiretroviral therapy resistance and increasing awareness of viral superinfections together with viral recombination, all of which are likely to impact on both HIV genetic variation and neuropathogenesis. With the persisting prevalence of HIV-induced neurocognitive disabilities, despite marked improvements in managing immunosuppression, it remains imperative to fully define and understand the mechanisms by which viral dynamics and diversity contribute to neurological disease, permitting the development of new therapeutic strategies.