Myocardial ischemia is a condition in which lack of blood flow to the cardiac muscle occurs resulting in deficient oxygen and nutrient supply to the heart. The restoration of blood flow to an organ or tissue is termed reperfusion. Brief episodes of ischemia and reperfusion given after prolonged ischemia and at the onset of reperfusion denotes postconditioning. Myocardial postconditioning is a phenomenon in which myocardium from lethal ischemia-reperfusion injury is protected. However, numerous experimental studies reveal that the cardioprotective effects of postconditioning are suppressed in various pathological states. This review critically discusses the mechanisms involved in the cardioprotective effects of postconditioning and factors affecting the cardioprotective potential of myocardial postconditioning.