Skin damage induced by UVR is an escalating problem in dermatology, and increasing incidence of skin cancer, especially for non-melanoma skin cancer, has been reported worldwide. UVR from sun exposure and the production of reactive oxygen species (ROS) is known to be a pivotal factor in the aetiology of skin cancer. The pineal hormone melatonin is recognized as the most potent endogenous antioxidant. Melatonin conducts its antioxidant effects acting directly as a radical scavenger and indirectly by up regulation of antioxidant enzymes. It has been proposed, that melatonin may have a protective effect against UVR-induced skin damage. The aim of this thesis was to: - Clarify melatonin's protective effect against UVR-induced skin damage in laboratory and clinical settings trough a systematic review of the literature. - To clinically assess the protective effect of topical treatment with melatonin against natural sun exposure, and determine the optimal concentration. - To clinically evaluate the degree of cognitive dysfunction with full body application of topical melatonin. Study 1: This was a systematic review using the databases Pubmed, EM-BASE and Cinahl. The databases were searched up to January 2013 to identify studies evaluating melatonin's protective effect against UVR-induced erythema in humans, and damage on a cellular level. Twenty studies were included, four human and 16 experimental. The results indicated that melatonin had a protective effect against UVR-induced erythema if applied before exposure, and this effect was probably obtained by melatonin acting directly as an antioxidant, and indirectly by regulating gene expression and inducing a DNA stabilizing effect. As these results were obtained using artificial UVR-sources and without investigating possible side effects, studies using natural sunlight and evaluating possible side effects of topical melatonin administration were warranted. Study 2: This study was a randomized, double-blind, placebo-controlled study. We evaluated the protective effect of three different doses of topical melatonin against erythema induced by natural sun-light. The primary outcome was reduction in erythema, evaluated by chromatography, after sun exposure, when treated with topi-cal melatonin (0.5%, 2.5%, 12.5%) versus placebo and no treatment. A significant difference in erythema formation was found between areas treated with melatonin 12.5% and areas receiving placebo or no treatment. However, this was only seen in participants with an erythema reaction to the sun exposure. Further-more, the treated skin areas were very small and studies assessing any potential adverse effects were necessary. Study 3: This also was a randomized, double-blind, placebo-controlled, cross-over study. We assessed the degree of cognitive dysfunction with full body application of topical melatonin 12.5%. Cognition was evaluated using a neuropsychological test battery consisting of Karolinska sleepiness scale (KSS), finger tapping test (FTT) and continuous reaction time (CRT). The impact on KSS was the primary outcome. We found no significant effect on cognition, however, large inter-individual variation was observed. These results support that melatonin is a safe drug for dermal application. The studies in this thesis may be valuable in the research field of melatonin's protective potential against UVR-induced oxidative skin damage. Increasing incidence of skin cancer is reported worldwide, and experts have suggested that the problem will only increase further, due to depletion of the ozone layer and the aging population. Furthermore, high-risk patient groups are emerging with the widely use of immunosuppressive medicine in various diseases, and this high-risk is in spite of use of protective measures known today. Therefore, development of new and more effective sun protective agents, with other qualities than simple chemical reflection of the UVR, is more important than ever. We have supported the suggestion of melatonin as a sun protective agent, and added the clinical relevant feature, that melatonin also has a protective effect against natural sunlight. Furthermore, we have supported the idea of melatonin being a safe drug for topical treatment, even in previous unknown high dosages. However, before any clinical implementation of melatonin as a sun protective agent can take place, further studies evaluating the long-term effects are warranted.