Abstract The same receptors for excitatory amino acids (EAA) that mediate direct neuronal depolarization can also be responsible for neuronal injury. Prolonged stimulation of EAA receptors of either the N-methyl-d-aspartate (NMDA) or non-NMDA types eventually results in the death of most central neurons. The exact mechanism(s) of cell injury is complicated, since depolarization and neuronal swelling, calcium influx, and possibly second messengers all contribute. Evidence is accumulating that the brain damage associated with anoxia, stroke, hypoglycemia, epilepsy, and perhaps neurodegenerative illnesses such as Huntington's disease may be at least partially produced by excessive activation of NMDA receptors. To the extent that the pathophysiology can be explained by this mechanism, it may be amenable to rational therapies now under development.