▪ Abstract  In the phenomenon termed "ischemic preconditioning," a brief period of ischemia prior to a more prolonged one improves myocardial function (after reperfusion) and diminishes infarction. This phenomenon has been described extensively in experimental animals and now in humans. It is triggered by several agents released by ischemic cells and can be reproduced by infusion of agonists coupled to protein kinase C (PKC), e.g. adenosine, angiotensin, phenylephrine, bradykinin, and endothelin. The intracellular signaling pathway involves a phospholipase, either C or D, which metabolizes membrane phospholipids to produce diacylglycerol, a necessary endogenous cofactor for PKC activation. Which protein(s) is phosphorylated by PKC is not yet known, nor is the identity of the end-effector that actually mediates protection of the ischemic cell. Identification of the end-effector may make it possible in the routine treatment of patients with ischemic heart disease to precondition and thereby salvage ischemic myocardium and improve survival.