The prevalence of HIV-associated neurocognitive impairment in perinatally HIV-infected children has declined since the introduction of combination antiretroviral therapy (cART). Early initiation of cART in infancy has been shown to positively impact neurodevelopment; however, children continue to be diagnosed with HIV outside of the early infancy period and can experience subtle to severe neurocognitive deficits despite cART. The causes of these neurocognitive deficits despite effective cART are multifactorial and likely include continued viral replication in the CNS, ongoing neuroinflammation, irreversible CNS injury prior to cART initiation, neurotoxic effects of cART, and socioeconomic and psychosocial effects. Many aspects of our understanding of HIV-associated neurocognitive disorders have emerged from research in adult patients, but perinatally HIV-infected children represent a very different population. These children were exposed to HIV during a period of rapid brain development and have lifelong infection and potential lifelong cART exposure. HIV is no longer a rapidly fatal disease, and most HIV-infected children in resource-rich countries are living into adulthood. It is therefore critical to optimize neurocognitive outcomes of these youth. This review summarizes current understanding of the pathogenesis of HIV-associated CNS infection and the impact of cART on neurocognitive function in children and adolescents and discusses important areas for future research. Copyright (c) 2014 John Wiley & Sons, Ltd.