The skin is the interface between the organism and the external environment, acting as its first barrier. Thus, this organ is constantly challenged by physical stimuli such as UV and infrared radiation, visible light, and temperature as well as chemicals and pathogens. To counteract the deleterious effects of the above-mentioned stimuli, the skin has complex defense mechanisms such as: immune and neuroendocrine systems; shedding of epidermal squamous layers and apoptosis of damaged cells; DNA repair; and pigmentary system. Here we have reviewed the current knowledge regarding which stimuli affect the molecular clock of the skin, the consequences to skin-related biological processes and, based on such knowledge, we suggest some therapeutic targets. We also explored the recent advances regarding the molecular clock disruption in melanoma, its impact on the carcinogenic process, and its therapeutic value in melanoma treatment.