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Melanin has several physiological roles in maintaining health, but, notably, it affects the synthesis of vitamin D. Melanin is the primary determinant of the degree of skin pigmentation and protects the body from harmful ultraviolet radiation. Synthesis of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) in the skin, however, is dependent on ultraviolet B light. Highly pigmented skin, to the level found in people of African origin, abrogates almost all ultraviolet-induced 1,25(OH)2D3 synthesis. Numerous animal models and clinical studies have underlined the essential role of vitamin D as a modulator of the different processes of the immune system. Evidence indicates that serum concentrations of 1,25(OH)2D3 and the prevalence of autoimmune diseases in a certain population are associated with the latitude at which that population resides. This article explores the relationship between skin pigmentation, vitamin D and the prevalence of autoimmune disease.Papers discussed in this Review were identified from the authors' databases and supplemented by searches on PubMed and online journals published between 1960 and 2008. Only full-text papers from peer-reviewed, English-language journals were included. The following keywords in various combinations were used in the searches: “melanin”, “vitamin D”, “autoimmunity”, “cytokines”, “SLE”, “rheumatoid arthritis”, “inflammatory disorders”, “vitamin D receptor” and “multiple sclerosis”.