Infarct size is determined not only by the severity of ischemia but also by pathological processes initiated at reperfusion. Accumulating experimental evidence indicates that lethal reperfusion injury might account for up to half of the final size of the myocardial infarct. Ischemic postconditioning (brief repeated periods of ischemia-reperfusion applied at the onset of coronary reflow) has been recently described as a powerful cardioprotection mechanism that prevents lethal reperfusion injury. This is the first method proven to reduce the final infarct size by about 50% in several in vivo models and to be confirmed in recent preliminary human studies. The molecular pathways are incompletely mapped but they probably converge to a mitochondrial key target: the mitochondrial permeability transition pore (PTP) which opening during early reperfusion is an event that promotes myocardial cell death. In different animal models and experimental settings, pharmacological PTP inhibition at the onset of reperfusion reproduces all the cardioprotective effects of ischemic postconditioning. In a recent proof-of-concept trial, the administration (just before percutaneous coronary intervention) of cyclosporine A, a potent PTP inhibitor, was associated with smaller infarct size. This review will focus on the physiological preclinical data on both ischemic and pharmacological postconditioning that are relevant to their translation to clinical therapeutics.