The skin is the only tissue yet known in which the complete ultraviolet-B (UV-B)–induced pathway from 7-dehydrocholesterol to hormonally active calcitriol (1α,25-dihydroxyvitamin D₃) occurs under physiological conditions. Epidermal synthesis of calcitriol could be of fundamental relevance because calcitriol regulates important cellular functions in keratinocytes and immunocompetent cells. Because of their antiproliferative and prodifferentiating effects, calcitriol and other vitamin D analogs are highly efficient in the treatment of psoriasis vulgaris. The known antipsoriatic effect of UV-B light could, at least in part, be mediated via UV-B–induced synthesis of calcitriol. In addition, mounting evidence indicates that cutaneous vitamin D₃ synthesis is of high importance for the prevention of a broad variety of diseases, including various malignancies. New but controversially discussed sun-protection guidelines were established for the prevention of internal cancers. A better understanding of the metabolism of vitamin D in the skin opens new perspectives for therapeutic applications of vitamin D analogs.