The skin has been recognized as the site for the sun-mediated photosynthesis of vitamin D3; until recently, however, very little was known about either the sequence of events leading to the formation of vitamin D3 in human skin or the factors that regulate the synthesis of this hormone. It is now established that, during exposure to sunlight, the cutaneous reservoir of 7-dehydrocholesterol (principally in the stratum Malpighii) converts to previtamin D3. Once this thermally labile previtamin is formed, it undergoes a temperature-dependent isomerization to vitamin D3 over a period of 3 days. The plasma vitamin-D binding protein preferentially translocates vitamin D3 from the skin into the circulation. During prolonged exposure to the sun, the accumulation of previtamin D3 is limited to about 10 to 15% of the original 7-dehydrocholesterol content because the previtamin photoisomerizes to 2 biologically inert photoproducts, lumisterol3 and tachysterol3. Increases in either latitude or the melanin concentration in the skin diminish the epidermal synthesis of previtamin D3. A single total body exposure to 3 minimal erythemal doses of ultraviolet radiation increased the vitamin-D3 levels in the serum 25-hydroxyvitamin-D levels after 7 days. The unique mechanism for the cutaneous synthesis, storage, and steady release of vitamin D3 into the circulation prompted an investigation into the potential therapeutic benefits of using the skin as the site for the synthesis and absorption of vitamin-D3 metabolites.