After an acute myocardial infarction (AMI), early reperfusion by thrombolysis or primary percutaneous coronary intervention remains the most-effective strategy for limiting the size of an evolving infarct. The mortality from AMI, however, remains significant, due partly to the lethal reperfusion injury that occurs on reperfusing the ischemic myocardium. Novel cardioprotective strategies are required to target this form of injury. In ischemic preconditioning transient, nonlethal episodes of myocardial ischemia and reperfusion before the index ischemic episode reduce infarct size. The cardioprotective potential of ischemic preconditioning has not been realized in clinical practice because it necessitates an intervention applied before the onset of AMI, which is difficult to predict. A more-amenable approach to cardioprotection is to intervene at the onset of reperfusion, the timing of which is under the control of the operator. In this regard, ischemic postconditioning, in which transient episodes of myocardial ischemia and reperfusion administered at the onset of reperfusion reduce infarct size, constitutes one such intervention. Interestingly, studies suggest that ischemic preconditioning and postconditioning activate the same signaling pathway at the time of reperfusion, thereby offering a common target for cardioprotection. Therefore, the pharmacologic recruitment of this signaling pathway at the time of myocardial reperfusion might allow one to harness the cardioprotective potential of ischemic preconditioning and postconditioning. In this review, we discuss the potential application of ischemic preconditioning and postconditioning in the clinical arena of myocardial ischemia and reperfusion, and examine the common signaling pathways by which this might be achieved.