Prompt reperfusion therapy in acute myocardial infarction enhances clinical outcome. However, reperfusion itself may contribute to myocardial cell death. The current review outlines the multifocal mechanisms of reperfusion injury and focuses on understanding the potential role of each element and its contribution to the injury pattern inflicted upon the myocardium. We evaluate the spectrum of contemporary therapies that have been tested in an attempt to reduce myocardial injury. Finally, we explore promising innovative strategies targeting novel reperfusion injury pathways to protect ischemic myocardium during reperfusion.