Reperfusion is the definitive treatment to reduce infarct size and other manifestations of postischemic injury. However, reperfusion contributes to postischemic injury, and, therefore, reperfusion therapies do not achieve the optimal salvage of myocardium. Other tissues as well undergo injury after reperfusion, notably, the coronary vascular endothelium. Postconditioning has been shown to have salubrious effects on different tissue types within the heart (cardiomyocytes, endothelium) and to protect against various pathologic processes, including necrosis, apoptosis, contractile dysfunction, arrhythmias, and microvascular injury or "no-reflow." The mechanisms by which postconditioning alters the pathophysiology of reperfusion injury is exceedingly complex and involves physiological mechanisms (e.g., delaying re-alkalinization of tissue pH, triggering release of autacoids, and opening and closing of various channels) and molecular mechanisms (activation of kinases) that affect cellular and subcellular targets or effectors. The physiologic responses to postconditioning are not isolated or mutually exclusive, but are interactive, with one response affecting another in an integrated manner. This integrated response on multiple targets differs from the monotherapy approach by drugs that have failed to reduce reperfusion injury on a consistent basis and may underlie the efficacy of this therapeutic approach across species and in human trials.