Brain ischemia due to a critical reduction in cerebral blood flow is a well recognized and common cause of irreversible brain damage. The observation that brain cells are more resistant to ischemia than was previously assumed on the basis of clinical experience has stimulated considerable investigative work designed to determine those factors responsible for irreversible ischemic cell damage. At this time, data from these investigations indicate that cellular acidosis and biochemical disturbances initiated by abnormal intracellular ion homeostasis may be especially important in determining the ultimate survival of nerve cells. This review examines the biochemical events initiated by ischemia and their potential role in determining the ultimate survival of brain cells.