Stroke is the third leading cause of death and the leading cause of adult disability in the United States. This review outlines the pathways that lead to cell death following stroke, and also summarizes the current literature on the phenomenon of ischemic tolerance. Ischemic tolerance is an endogenous neuroprotective mechanism by which neurons are protected from the deleterious effects of brain ischemia that occur during and after stroke. A better understanding of the processes that lead to cell death after stroke and endogenous neuroprotective mechanisms like ischemic tolerance could help in the development of new treatment strategies for this devastating neurological disease.