Based on extensive investigation of melatonin in human cell models (keratinocytes, fibroblasts), a great variety of melatonin actions, mechanisms, intracellularly localized synthesis and metabolism as well as receptor expression has been unravelled, identifying melatonin as a key player in cutaneous biology and dermato‐endocrinology. Melatonin was reported to act directly protective as a radical scavenger in many conditions of skin‐related stress (ultraviolet radiation, ionizing radiation, thermal injury, ulcer formation, skin flap necrosis) and to modulate cell growth via membrane (MT1, MT2), cytosolic (MT3/NQO2) and nuclear receptors (RORα). Membrane and nuclear melatonin receptor expression is hair cycle dependent in murine hair follicles, whereas estradiol receptor (ERα) expression is down‐regulated by melatonin. Furthermore, the modulation of secondary endocrine signalling (e.g. prolactin release, estrogen receptor‐mediated signalling) in the skin is mediated by melatonin. Melatonin levels of magnitudes higher than in the plasma have been detected in human keratinocytes and murine and human hair follicles, whereby noradrenalin, the classical stimulator of melatonin synthesis, increased melatonin production in hair follicles. Additionally, a melatoninergic antioxidative system (MAS) of the skin has been identified with UV‐enhanced formation of melatonin metabolites, 2‐OH‐melatonin and AFMK, the latter being a strong antioxidant itself. Alternatively, melatonin indirectly protects cells by up‐regulating gene expression and activity of non‐melatonin autonomous protective systems, the intracellular antioxidative enzyme network which is composed of Mn‐SOD, Cu‐Zn‐SOD, CAT and GPx. To further drive melatonin research towards the human organism level, two human organ culture models have been choosen or newly established i) the human hair organ culture model and ii) the human full thickness skin model, respectively. Two crucial stressors of human skin/hair biology are used to investigate their morphology and functional effect expression in these models: ultraviolet radiation and chemotherapy‐induced cytotoxicity. Standardized stress conditions in both models serve to investigate differential expression of stress levels, their time‐dependent dynamics and effect quality. Finally, reduction of UV‐damaged keratinocytes (sun‐burn cells) by melatonin in the full‐skin organ model and anti‐apoptotic effects in chemotherapy‐induced hair follicle damage have been observed.