Primary percutaneous coronary intervention is the recommended therapy for patients with STelevation myocardial infarction. However, restoration of coronary blood flow may lead to reperfusion injury, which has been suggested to account for 50% of the final myocardial infarct size. As an adjuvant therapy to primary percutaneous coronary intervention, ischemic postconditioning (IPost) has been shown to be safe and to underlie cardioprotection in several clinical trials. However, there remain important issues to be settled before IPost can be used routinely in patients undergoing primary percutaneous coronary intervention: first, determining which IPost protocol is the most optimal in humans; second, determining the effect of IPost on clinical outcome; third, determining in which patients should IPost be applied; and fourth, determining the effect on left ventricular function. This article discusses these issues with a clinical perspective and looks into alternative pharmacological cardioprotection.