Despite the large number of novel therapies under basic scientific investigation, the translation of cardioprotective strategies targeting reperfusion injury to improve patient outcomes following percutaneous coronary intervention (PCI) for myocardial infarction (MI) has been disappointing. The varying susceptibility of an individual to reperfusion injury, as well as the narrow window of opportunity in which to intervene, adds significant complexity. Here, we discuss the unmet need and challenges of translating cardioprotective strategies into clinical practice, review the pathophysiology of microvascular dysfunction and lethal reperfusion as they relate to promising novel therapeutics, and evaluate recent and ongoing clinical trials in the field.