Reperfusion therapy is the primary treatment of acute myocardial infarction and must be applied as soon as possible to limit the ischemic insult. Unfortunately, reperfusion is responsible for additional myocardial damage likely involving opening of the mitochondrial permeability transition pore. Ischemic postconditioning is a powerful intervention that dramatically reduces lethal reperfusion injury. Several clinical studies using angioplasty postconditioning now support its protective effects in patients with an acute myocardial infarction. Alternatively, pharmacological postconditioning could afford comparable protection and be applied to a much larger number of patients. Indeed, the mitochondrial permeability transition pore inhibitor cyclosporine A has been shown to generate a similar protection in acute myocardial infarction patients. Future large-scale trials are needed to determine whether angioplasty or pharmacological postconditioning may improve clinical outcome in STEMI patients.