Theory and hypotheses Because there is strong evidence that free radicals contribute to post-ischemic injury, antioxidant enzyme therapy could potentially be extremely effective in reducing the cellular damage. In reality, however, the usefulness of this therapy is limited by a number of factors, in particular the ability of the antioxidants to penetrate the cell membrane and to scavenge free radicals in situ. Fortunately, this limitation can, in part, be addressed with the use of melatonin, a potent indirect and direct free radical scavenger that easily diffuses through the cell membrane to exert its antioxidant effects in all compartments of the cell. Indeed, in contrast to the partial of distribution of other antioxidants, such as vitamin C or E, the melatonin distributes it readily in all subcellular compartments owing to its double-solubility in both, aqueous and in lipid environment. Several recent publications present evidence that the newly discovered antioxidant melatonin has significant protective actions against the cardiac damage such as occurs during ischemia-reperfusion injury.