Reperfusion of an occluded coronary artery is the most effective intervention in reducing cardiac injury which occurs as a consequence of an acute myocardial infarction. However, reperfusion per se may exacerbate the extent of myocardial injury which started at the onset of ischemia, thus leading to the so-called "reperfusion injury". The published studies in the last few years provide new hopes on the mitochondrion and its role in ischemia/reperfusion injury, through the modulation of the mitochondrial permeability pore. After very encouraging experimental data, two clinical trials are presented, CIRCUS and CYCLE, which should help addressing the still outstanding question: may an intervention targeted to decrease the permeability of the mitochondrial pore during reperfusion reduce infarct size and improve clinical outcomes of patients with myocardial infarction undergoing primary percutaneous coronary intervention?