Human immunodeficiency virus (HIV) infection in the United States and increasingly in other parts of the world is now being driven by drug-abusing populations. Both HIV infection and drugs of abuse affect the basal ganglia, hippocampal structures, and the prefrontal cortex. Understanding the interactions between the two and their combined effects is critical. In vitro studies show that opiates, methamphetamine, and cocaine can potentiate HIV replication and can enhance or synergize with HIV proteins to cause glial cell activation, neurotoxicity, and breakdown of the blood-brain barrier. Many of these studies have been confirmed in vivo by using rodent models. However, the complexities of polydrug addiction and drug withdrawal have yet to be examined in simian models of HIV-associated neurocognitive disorder. Clinical studies in substance-abusing, HIV-positive patients pose multiple challenges whether aimed at studying disease pathogenesis or conducting clinical trials. This review examines the literature to date, lists the experimental challenges faced by researchers studying effects of drug addiction on HIV neuropathogenesis, and suggests future directions for research.