The mechanisms underlying cell damage in stroke or during experimental brain ischemia are not fully understood. L-Cysteine, an excitotoxic amino acid that could contribute to tissue damage, is normally found in relatively low levels in brain (ca. 0.05 mumol/g), compared to the cysteine-containing tripeptide, glutathione (GSH, ca. 1.5 mumol/g). We have observed that during brain ischemia in gerbils, levels of cysteine rise 10-13-fold over an 8 h period to 0.66 and 0.62 mumol/g, respectively, in the ischemic hippocampus and striatum. At the same time, levels of GSH fall by 0.84 and 0.94 mumol/g, respectively. The elevated free cysteine may be derived largely from GSH. The levels of cysteine found in ischemic brain are similar to those reported after parenteral administration of neurotoxic doses of L-cysteine to perinatal rats. The remarkable increase in cysteine during brain ischemia, coupled to its neurotoxic properties, may play a role in aspects of brain damage during or following brain ischemia.