Neuropsychological dysfunction, ranging from mild cognitive symptoms to dementia has been a consistent part of the clinical picture of HIV/AIDS. However, advances in clinical management, particularly antiretroviral (ARV) treatment, have mitigated the neuropsychological effects of HIV and revised the pattern and nature of cognitive deficits, which are observed in HIV-infected individuals. The attendant improvements in mortality and morbidity have led to a need for programs and interventions that sustain healthy behavior and prevent a resurgence of HIV transmission risk. Psychiatric risk factors, particularly substance use, which often contribute to initial acquisition of HIV, still require attention. These risk factors may also exacerbate neuropsychological dysfunction and compromise adherence to prevention recommendations and treatment. Specifically, a more complete understanding of the effects of substance abuse on the progression of HIV related cognitive decline can inform evaluation and management of HIV seropositives with concurrent substance use disorders. This review provides an overview of the neuropsychology of HIV and substance abuse and the extant research that has examined the effects of both HIV disease and substance use on neuropsychological functioning and implications for treatment and future research.