INTRODUCTION: The neurohormone melatonin is secreted by the pineal gland and shows a circadian rhythm. It has been used in pathological conditions to evaluate its protective capacity against disease, often in connection to oxidative stress. The abundance of cases reported suggests that the mechanisms of action through which melatonin confers this protection may be linked to other molecular targets besides its G-protein-coupled receptors or its intrinsic scavenging capacity. AREAS COVERED: In this review, 300 melatonin-induced protection cases are collated together with basic facts about melatonin. Some of the experimental results lead us to believe that, at high 'pharmacological' concentrations (500 µM and beyond), melatonin inhibits the 'newly' discovered target, quinone reductase 2 (QR2). It is possible that QR2 acts through its specific capacity to reduce orthoquinone to particularly unstable chemical species, which cycle spontaneously back to orthoquinone. This process generates high quantities of radical oxygen species, which are associated with many diseases states, such as inflammation. Therefore, inhibition of QR2 could explain some of the protective activities of melatonin. EXPERT OPINION: The tools have been generated to further study this particular and singular mechanism of action of melatonin. The property of QR2 inhibition could unify the many aspects of melatonin action reported in the literature.