A brief episode of ischemia renders the brain resistant against subsequent, longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. After global cerebral ischemia, ischemic tolerance may protect up to 90% of hippocampal CA1 neurons. In focal ischemia, this phenomenon reduces infarct volume by 20-60%. However, the basic molecular mechanisms of ischemic tolerance are largely unknown. During the induction phase, N-methyl-d-aspartate (NMDA) and adenosine receptors and, possibly, oxygen free radicals and conservation of energy metabolism are required. Protein kinases, transcription factors, and immediate early genes appear to transduce the signal into a tolerant response. Ischemic tolerance can be observed in different phases. The early phase lasts for several hours after the preconditioning stimulus and adenosine receptors and ATP-dependent potassium channels play a role similar to that in cardiac ischemic tolerance. The delayed protection, retained for a maximum of 2-4 days, currently is best explained by genetic remodeling with expression or repression of multiple genes. Several candidates have been identified to date, among them heat-shock proteins, cytokines, and antioxidant enzymes. Several studies have shown that angina pectoris before myocardial infarction represents a clinical correlate of experimental preconditioning protocols. Accordingly, evidence for a possible protective effect of transient ischemic attacks (TIAs) occurring before stroke are accumulating.