Neuronal injury caused by ischemia after occlusion of cerebral arteries is believed to be mediated by excessive activation of glutamate receptors. In the ischemic brain, extracellular glutamate is elevated rapidly after the onset of ischemia and declines following reperfusion. The mechanisms of the elevation of extracellular glutamate include enhanced efflux of glutamate and the reduction of glutamate uptake. The early efflux of glutamate occurring immediately after the onset of ischemia is mediated by a calcium-dependent process through activation of voltage-dependent calcium channels. The calcium-independent efflux at later stages is thought to be mediated primarily by glutamate transporters operating in the reverse mode owing to the imbalance of sodium ions across plasma membranes. Although high levels of glutamate in the extracellular space are well established to appear rapidly after the onset of ischemia, a direct linkage between the enhanced release of glutamate and the neuronal injury has not been fully established. In cultured neurons, ischemia induces efflux of glutamate into the extracellular space, but subsequent neuronal loss is not solely caused by the high glutamate concentration. In addition, cultured neurons can be rescued by NMDA antagonists added to the medium after exposure to glutamate receptor agonists. Two mechanisms can be proposed for neuroprotection by late NMDA receptor blockade, i.e., blocking of presynaptic release of glutamate after excessive activation of glutamate receptors, and blocking of postsynaptic sensitization of NMDA receptors.