Calcitriol (1alpha,25(OH)2D3), the hormonally active form of vitamin D3 (D3) is produced by a cascade of reactions, including photochemical D3 synthesis in the skin and subsequent hydroxylation at the C-25 atom in the liver and finally at C-1alpha position in the kidney. However, there is substantial evidence for additional extrarenal sites of calcitriol synthesis. In vitro, many nonrenal cells, including bone, placenta, prostata, keratinocytes, macrophages, T-lymphocytes and several cancer cells (e.g., from lung, prostata and skin) can enzymatically convert calcidiol (25OHD3) to 1alpha,25(OH)2D3. We have demonstrated that keratinocytes of the skin have unique properties in the D3 pathway; they are not only capable of producing D3 from 7-dehydrocholesterol (7-DHC), but also generate 1alpha,25(OH)2D3 from the substrates 25OHD3, lalpha-hydroxyvitamin D3 (1alpha-OHD3) and even D3. It is evident that keratinocytes possess at least 1alpha-OH-, 25OH- and 24OHase activity, which is necessary for enzymatic conversion of D3 to 1alpha,25(OH)2D3, and the 24OHase activity for initiation of catabolism of 1alpha,25(OH)2D3 to more polar metabolites. Thus, the skin is apparently the only extrarenal tissue where the complete UVB-induced pathway from 7-DHC to 1alpha,25(OH)2D3 takes place under physiological circumstances.