Reperfusion therapy is the indispensable treatment of acute myocardial infarction (AMI) and must be applied as soon as possible to attenuate the ischemic insult. Evidence indicates that reperfusion is responsible for additional myocardial damage likely involving opening of the mitochondrial permeability transition pore. Ischemic postconditioning is a new way to dramatically reduce the lethal reperfusion injury. Several clinical studies using angioplasty postconditioning now support its protective effects in patients with an AMI. An interesting alternative is pharmacological postconditioning, which could be applied to a much larger number of patients. The mitochondrial permeability transition pore inhibitor cyclosporine A has been shown to generate a comparable protection in AMI patients. Future large-scale trials are needed to determine whether postconditioning may improve clinical outcome in ST-segment elevation MI patients.