AbstractCell death caused by hypoxia‐ischemia appears to be due to multiple mechanisms causing lysis of cells, both by osmotic rupture and by calcium‐dependent activation of degradative processes, as well as apoptosis. In the case of osmotic and calcium‐dependent lysis, the triggering stimulus seems to be abnormal accumulation of glutamate in the extracellular space. In the case of apoptotic death, the triggering stimulus is unclear. Because activation of one or more death programs does not necessarily commit a cell to die, a therapeutic window exists in which it should be possible to intervene to prevent progression to cell death in many cells that are affected by an hypoxic‐ischemic episode. Several therapeutic approaches have emerged targeting various steps in the process set in motion by abnormal glutamate accumulation. In addition, other approaches need to be developed to block apoptotic cell death. The most efficacious forms of therapy will probably be those that are effective against all types of cell death triggered by hypoxia‐ischemia. This may be accomplished either by the use of multiple agents or by intervention targeting processes or intermediates shared by multiple mechanisms of cell death. MRDD Research Reviews 3:76–84, 1997. © 1997 Wil