Currently, there is increasingly more data on extrapineal foci of melatonin synthesis and the existence of tissue-specific local melatonergic systems, which play a specific biological role in countering specific tissue stressors in situ. The skin is the largest organ in the body of mammals, which is involved in extrapineal synthesis of melatonin. The whole integument is exposed to a constant influence of the external environment, and its functioning is under the central control of the regulating and synchronizing structures of the central nervous system. In mammals, all circadian processes of life regulation are subject to central control, but the skin is additionally regulated by its own peripheral oscillators. The central clock is located in the suprachiasmatic nucleus of the hypothalamus and transmits circadian information to the integument using clock genes and proteins through sympathetic innervation signals, as well as through secreted hormones. At the skin level, melatonin acts as an antioxidant and cytoprotective agent and also plays a fundamental role in maintaining skin homeostasis. Cutaneous melatonergic system can act as an autocrine or paracrine protector against environmental damage. Melatonin can reduce or counteract environmental and endogenous stresses, while maintaining the integrity of the skin.