The treatment of AMI centers on prompt reperfusion.1 Although the benefits of reperfusion are unquestioned, some of the benefits can be lost because of injury occurring in the myocardium during the early phases of reperfusion.2 The present study shows for the first time that inhibition of ASK1 during AMI through the use of a pharmacological inhibitor optimizes the benefits of reperfusion by limiting reperfusion-mediated cellular injury in an in vivo model of regional transient myocardial ischemia. Here, MAP3K5 is linked to myocardial ischemia.