: During the last decade, attention was concentrated on melatonin -- one of the hormones of the diffuse neuroendocrine system, which has been considered only as a hormone of the pineal gland, for many years. Currently, melatonin has been identified not only in the pineal gland, but also in extrapineal tissues -- retina, harderian gland, gut mucosa, cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, ovary, carotid body, placenta and endometrium as well as in non-neuroendocrine cells like mast cells, natural killer cells, eosinophilic leukocytes, platelets and endothelial cells. The above list of the cells storing melatonin indicates that melatonin has a unique position among the hormones of the diffuse neuroendocrine system, which is present in practically all organ systems. Functionally, melatonin-producing cells are certain to be part and parcel of the diffuse neuroendocrine system as a universal system of response, control and organism protection. Taking into account the large number of melatonin-producing cells in many organs, the wide spectrum of biological activities of melatonin and especially its main property as a universal regulator of biological rhythms, it should be possible to consider extrapineal melatonin as a key paracrine signal molecule for the local coordination of intercellular relationships. Analysis of our long-term clinical investigations shows the direct participation and active role of extrapineal melatonin in the pathogenesis of tumor growth and many other non-tumor pathologies such as gastric ulcer, immune diseases, neurodegenerative processes, radiation disorders, etc. The modification of antitumor and other specific therapy by the activation or inhibition of extrapineal melatonin activity could be useful for the improvement of the treatment of illness.