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Melatonin was discovered by Lerner and Coworkers in 1958, and is the main product secreted by the pineal gland. It is a phylogenetically highly conserved molecule and one of the oldest biological signaling mechanisms. It presents several biological functions, among them the most studied is the regulation of the sleep cycle and wakefulness. In addition, melatonin acts as an immunomodulatory, antioxidant molecule and has anticarcinogenic potential. It also participates in the regulation of mood and control of seasonal reproduction. Melatonin is a potent free radical scavenger and several of its metabolites have the ability to remove singlet oxygen, superoxide radicals, hydroperoxides, hydroxyl radicals and radical lipid peroxides. It easily penetrates cell membranes by being soluble in aqueous and organic media, playing a key role in cell biology. Although their activities are interesting for therapy, their low availability, short half-life, and rapid metabolism restrict their use. In this sense, nanotechnology is a tool that has been studied for the elaboration of systems that improve the pharmacokinetic and pharmacodynamic characteristics of melatonin, in order to potentiate its application in biological models. This review summarizes several studies published in recent years that have shown the most numerous biological activities of melatonin and the improvement of their therapeutic potential through nanotechnology.