HIV infection of the central nervous system (CNS) can result in neurologic dysfunction with devastating consequences in a significant number of individuals with AIDS. Two main CNS complications in individuals with HIV are encephalitis and dementia, which are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, blood-brain barrier (BBB) disruption, and eventual damage and/or loss of neurons. One of the major mediators of NeuroAIDS is the transmigration of HIV-infected leukocytes across the BBB into the CNS. This review summarizes new key findings that support a critical role of the BBB in regulating leukocyte transmigration. In addition, we discuss studies on communication among cells of the immune system, BBB, and the CNS parenchyma, and suggest how these interactions contribute to the pathogenesis of NeuroAIDS. We also describe some of the animal models that have been used to study and characterize important mechanisms that have been proposed to be involved in HIV-induced CNS dysfunction. Finally, we review the pharmacologic interventions that address neuroinflammation, and the effect of substance abuse on HIV-1 related neuroimmunity.