Circulatory arrest and stroke are among the leading causes of death and disability worldwide, and they are difficult to treat. Only a limited number of therapeutic approaches have reached the bedside (eg, hypothermia and recombinant tissue plasminogen activator)1 and, unfortunately, relatively few patients are eligible. Virtually all experimental compounds tested so far have failed at some stage of translational development. Preconditioning is an attractive strategy that makes the brain and other visceral organs relatively resistant to tissue injury. It develops when a noxious stimulus, below the damage threshold, leads to reduced tissue injury on subsequent challenge with a stimulus given above injury threshold. It is an appealing strategy to identify novel endogenous protective mechanisms and, as demonstrated by Jensen, Loukogeorgakis, and their colleagues in this issue of Circulation ,2 it may prove useful to prevent brain damage in the clinical context when there is a high probability of cerebral ischemia (eg, before high-risk surgery or in patients with subarachnoid hemorrhage). Article see p 714 Various types of preconditioning stimuli have been used experimentally to protect brain, heart, retina, liver, kidney, and other organs.3 Some use ischemic preconditioning, in which the blood supply to a target organ is temporarily interrupted before introducing a longer infarct-generating insult that would ordinarily produce infarction; other studies use hypoxic preconditioning, in which animals are exposed to oxygen levels around 8% to 9% for a few hours. But ischemia and hypoxia are just 2 examples in a larger list of strategies that induce tolerance to brain injury: hypoglycemia, hypoxia, kainate-induced seizures, and exposure to volatile anesthetics, to name a few.4 Preconditioning can protect the brain either rapidly after stimulation (known as early, first window, or classical preconditioning) or after a 24-hour delay to induce protein synthesis-dependent protection lasting up to 96 hours …