The blood brain barrier (BBB) serves as a protective mechanism for the brain. It prevents entry of pernicious substances, whether chemical or cellular, from free access to the CNS. In essence, it is a defense mechanism preserving the internal milieu of the brain. The BBB may be disrupted by a number of pathological processes. CNS infection is a well recognized cause of BBB disruption. Among the CNS infections demonstrated to affect the BBB is human immunodeficiency virus (HIV). HIV infects the brain shortly after its acquisition. Studies of cerebrospinal fluid (CSF) as well as dynamic studies of contrast enhanced magnetic resonance imaging have confirmed abnormalities of the BBB in HIV-infected persons. Pathological studies of the CNS have confirmed the in vivo studies, and in vitro studies have identified a range of pathogenic mechanisms of HIV-associated BBB compromise. This disruption of the BBB may not only contribute to accelerating brain infection by HIV, but may also alter CNS function. Additionally, BBB disruption has implications with respect to antiretroviral therapy. This review will address these issues.