Over the past decade, the therapeutic strategies for acute myocardial infarction have changed considerably. Progress in experimental models, as well as noninvasive myocardial imaging techniques, has identified myocardial reperfusion injury as a significant contributor to the final infarct size in human patients. Following 3 decades devoted to the improvement of reperfusion therapy, recent major advances in myocardial protection after reperfusion slowly move the attention from the vessel to the muscle. In the past 20 years, several pharmacologic treatments or techniques applied at early reperfusion have been tested in experimental models and in the clinical setting. Numerous promising therapies in experimental models have failed to show significant benefit in the clinical realm. But to date, ischemic postconditioning applied at the onset of reperfusion is among the most promising therapies to treat reperfusion injury in myocardial infarction patients, with a 35% significant reduction of final infarct size in small groups of patients and different settings. However, clinical evidence in large population studies is still lacking for their widespread usage in the catheter laboratory at the time of reperfusion. After a brief review of the underlying molecular mechanisms of ischemic postconditioning, this review will focus on the clinical studies assessing the postconditioning effect in STEMI patients and review the findings and explore the future of this technique.