Endogenous myocardial protection refers to the natural defense mechanisms available to the heart to withstand an ischemic injury. So far, these mechanisms have been shown to encompass two phenomena most likely interrelated: ischemic preconditioning and stress protein synthesis. Ischemic preconditioning can be defined as the adaptive mechanism induced by a brief period of reversible ischemia increasing the heart's resistance to a subsequent longer period of ischemia. The therapeutic exploitation of these natural adaptive mechanisms in cardiac surgery is an appealing prospect, as preconditioning could be used before aortic cross-clamping to enhance the current methods of myocardial protection. Two major conclusions emerge from the bulk of experimental data on preconditioning: First, the adaptive phenomenon reduces infarct size after regional ischemia in animal preparations across a wide variety of species but its effects on arrhythmias and on preservation of function after global ischemia are less consistent. This is relevant to cardiac surgery where postbypass pump failure is more often due to stunning than to discrete necrosis. Second, regardless of the various components of the intracellular signaling pathway elicited by the preconditioning stimulus, it seems that the major mechanisms by which this pathway leads to a cardioprotective effect are a slowing of adenosine triphosphate depletion and a limitation of acidosis during the protracted period of ischemia. If the latter is true, then it can reasonably be predicted that these energy-sparing and acidosis-limiting effects may become redundant to those of cardioplegia. From these observations, it can be inferred that preconditioning may find an elective indication in situations where the potential for suboptimal protection increases the risk of necrosis (extensive coronary artery disease, severe left ventricular hypertrophy, long ischemic time, and beating heart operations where occlusion of the target vessels leads to unprotected distal ischemia). Since an ischemic preconditioning stimulus could be clinically undesirable, it is critically important to identify the endogenous mediators of the phenomenon in order to use them therapeutically. One of the most important of these mediators seems to be the adenosine triphosphate-dependent potassium channel. Currently, however, the clinical application of these drugs is hampered by their poor cardioselectivity which could result in untoward systemic vasodilatory effects before cardioprotection becomes manifest. Thus, although the modalities of pharmacologically induced preconditioning still remain to be determined, the concept of therapeutic exploitation of the endogenous adaptive mechanisms of the heart could potentially represent an important adjunct to our current techniques of myocardial protection.