Due to its small size and amphiphilic nature, indoleamine melatonin is able to reach all cell compartments quickly. The highest Melatonin concentrations are to be found in the mitochondria, and cytochrome c (cyt c) represents a Melatonin target, since Melatonin is able to oxidise organic molecules in the presence of physiological amounts of hydrogen peroxide (H2O2). The mitochondrial cyt c-mediated oxidation of melatonin depends on oxoferrylheme in two oneelectron steps. The protective effects of Melatonin against cardiac ischemia/reperfusion (I/R)-induced mitochondrial oxidative damage are well documented as an antioxidant agent which prevents and/or modulates the production of reactive oxygen species (ROS) responsible for the reperfusion injury. On the basis of our previous studies on ischemia/reperfusion (I/R) in human cardiomyocytes it has become clear that severe hypoxic and ischemic stimuli evoke a mitochondrial response in terms of the functional adaptation of cyt c oxidase (COX) to oxygen altered availability. Most, if not all, data are compatible with a mechanism of adaptation, in which nitric oxide (NO) generation is now considered as the major player. The NO-induced COX inhibition represents a key point in ischemia-induced, adaptive changes, since a balanced oxidative metabolism between lower O2 concentrations and COX catalytic capacity down-regulation is thus obtained. This mechanism is a limiting factor in the cardiac ischemia-induced ROS mitochondrial generation. In the light of this concept and if we consider melatonin to be strongly active in cyt c up-regulation, it is obvious that the use of this molecule in the course of cardiac ischemia could be deleterious. On the contrary, the prompt restoration of the coronary blood flow is inexorably associated with the so-called “reperfusion syndrome” and/or with a condition of myocardial stunning. These phenomena are strictly linked to the aforementioned ischemia-induced cyt c adaptive changes, for the reason that a primary imbalance is induced between the persistent down-regulated enzymatic oxidative capacity and mitochondrial oxygen gradients are rapidly restored. This leads to a massive ROS neo-generation, which evokes well-known cellular disorders. In this scenario the melatonin treatment could play a pivotal role in terms of a cyt c up-regulating agent, crucial for counteracting most, if not all the biochemical and molecular phenomena, on which the clinical symptoms proper of myocardial reperfusion syndrome are based.