<p>Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Primary percutaneous coronary intervention (PPCI) is the gold standard treatment for patients presenting with ST-segment elevation myocardial infarction (STEMI). PPCI reperfusion therapy has the potential to reduce infarct size, preserve the left ventricle ejection fraction (LVEF), prevent lethal complications, and improve prognosis. A significant proportion of STEMI patients, however, develop post-infarct heart failure despite optimal PPCI. One of the reasons for post-infarct heart failure is that reperfusion injury increases the infarct area after PPCI. This article reviews the current understanding and up-to-date evidence basis for therapeutic intervention of reperfusion injury. Specifically, the combination of myocardial ischemia secondary to acute coronary occlusion and reperfusion injury leads to further myocardial injury and cell death. Multiple treatment modalities have been shown to be cardioprotective and reduce reperfusion injury in experimental animal models. Recent clinical trials have assessed multiple cardioprotective strategies, including ischemic pre- and post-conditioning, pharmacologic therapies, and mechanical devices. While several therapies have been shown to reduce infarct size in animal models or proof-of-concept studies, many large-scale trial results have proven inconsistent and disappointing. To decrease the incidence of severe heart failure in patients and extend healthy life expectancy in an aging society, further development of prevention strategies for reperfusion injury is needed, including novel maneuvers, drugs, devices, and combinations of the three.</p>