A significant number of people infected with the human immunodeficiency virus (HIV) develop neurologic complications. The AIDS dementia complex is frequently accompanied by HIV encephalitis, which is characterized at the neuropathologic level by loss of neuronal subpopulations in the neocortex, limbic system, and basal ganglia in association with synaptic and dendritic damage, astrogliosis, and formation of microglial nodules and multinucleated giant cells. Recent studies have shown that the extent of neurodegeneration in this condition correlates directly with the amount of HIV-1 antigen in the brain. HIV-1 infection of the brain could result in neurodegeneration via neurotoxic effects of viral products (e.g., gp 120, Nef, Tat) and/or via alterations in the expression of host factors. The latter may include increased production of potentially detrimental factors such as cytokines, excitotoxic amino acids, free oxygen radicals, and bioactive lipid mediators as well as interference with the production or action of neurotrophic/protective factors. Derangements of the neuronal calcium homeostasis, lipid peroxidation, and induction of programmed cell death (apoptosis) may all play a role as final common pathogenetic pathways in HIV-1-induced neurodegeneration. Recent studies in transgenic mice (over)expressing HIV- or host-derived proteins in their central nervous system indicate that distinct neuronal populations may differ in their susceptibility to specific pathogenic factors. For example, glutamate-receptor-bearing pyramidal neurons were particularly susceptible to neurodegeneration promoted by HIV-1 products, whereas interneurons were more sensitive to the neurotoxic effects mediated by cytokines. For the design of effective treatments for the HIV-1-associated cognitive/motor complex, it will be important to determine whether the neurologic deficits in this entity result from global neuronal dysfunction or relate more specifically to the impairment of distinct neuronal subpopulations. It will also be critical to examine diverse in vitro and in vivo models to help decide which of the many pathogenetic processes that may be at work in this complex disease constitute the most promising therapeutic targets.