Over the past two decades, it has been demonstrated in various animal species that the myocardium possesses innate adaptive mechanisms that may render it more resistant to ischemic injury. Ischemic preconditioning, defined as the protection conferred to ischemic myocardium by prior episodes of brief sublethal ischemia, is one of the most potent of such adaptive phenomena. Extensive research over the past decade has alluded to the cellular mechanisms underlying this powerful means of reducing myocardial ischemia-reperfusion injury. Moreover, the possibility that such adaptive mechanisms might be inducible in the human heart has generated considerable excitement and enthusiastic research, which has significantly enhanced our understanding of the pathogenesis of ischemia-reperfusion injury. An insight into the mechanisms underlying the cardioprotective properties of ischemic preconditioning has, on the one hand, directed research aimed at identification of novel therapeutic agents for the treatment of ischemic heart disease, and on the other, questioned the use of potentially deleterious agents that may abolish the cardioprotective actions of ischemic preconditioning in patients with angina. Current studies are under way to evaluate the potential protection afforded by these "preconditioning" agents in patients with acute coronary syndromes, and some early reports provide some basis for optimism that a beneficial and clinically detectable improvement in myocardial protection may be possible. This article reviews our current knowledge of the cellular mechanisms responsible for mediation of ischemic preconditioning, the evidence for the existence of this phenomenon in humans, and its potential therapeutic applications.