The mechanism by which infection with the human immunodeficiency virus (HIV) leads to injury and dysfunction within the central nervous system (CNS) is not completely understood. Most studies support the hypothesis that neurons are impacted as bystander cells in a tissue environment made hostile by the innate and adaptive immune responses to chronic HIV infection within CNS tissue. The tumor suppressor transcription factor p53 participates in multiple cellular processes within the HIV infected CNS, and experimental evidence suggests that the resulting neurodegeneration occurs by induction of p53-mediated apoptotic pathways. Here we review the evidence for p53 as a participant in the responses of multiple CNS cell types to the presence of HIV and propose the hypothesis that HIV induced alterations in the CNS extracellular milieu converge at neuronal p53 activation.