HIV-1-associated Dementia (HAD) is a significant consequence of HIV infection. Although multiple inflammatory factors contribute to this chronic, progressive dementia, excitotoxic damage appears to be an underlying mechanism in the neurodegenerative process. Excitotoxicity is a cumulative effect of multiple processes occurring in the CNS during HAD. The overstimulation of glutamate receptors, an increased vulnerability of neurons, and disrupted astrocyte support each potentiate excitotoxic damage to neurons. Recent evidence suggests that poorly controlled generation of glutamate by phosphate-activated glutaminase may contribute to the neurotoxic state typical of HAD as well as other neurodegenerative disorders. Glutaminase converts glutamine, a widely available substrate throughout the CNS to glutamate. Inflammatory conditions may precipitate unregulated activity of glutaminase, a potentially important mechanism in HAD pathogenesis. © 2006 Association for Research in Nervous and Mental Disease.