Glutamate, a major excitatory transmitter substance, is neurotoxic at high concentrations. Brain dialysis experiments have demonstrated an extracellular overflow of glutamate during ischemia, and there is good evidence from several animal models that glutamate antagonists offer partial protection against the development of ischemic cell degeneration. These and other experimental data indicate that glutamate may be involved in the pathogenesis of ischemic brain damage. Quantitative immunocytochemical investigations carried out in the authors' laboratory suggest that ischemia is associated with loss of glutamate from nerve cell bodies, and reduced ability of the glial cells to metabolize glutamate. We discuss possibilities of new therapeutic strategies.