Our understanding of the mechanism of action of vitamin D has been broadened by the discovery of the extrarenal 1α-hydroxylase (CYP27B1) in various vitamin D target tissues around the body and the implications of this for the putative paracrine actions of 1α,25-dihydroxyvitamin D₃. This review updates our current knowledge of the cytochrome P450-mediated steps of vitamin D activation (CYP2R1, CYP27B1) and inactivation (CYP24A1, CYP3A4) and the newest physiological roles of vitamin D. The review goes on to examine how well exogenously supplied vitamin D compounds, whether dietary vitamin D₂ supplements or prescribed vitamin D analogs, substitute for their natural counterparts; how in some cases vitamin D can be used in conjunction with vitamin D analogs; and the overall impact of these supplements and drugs on the components of the vitamin D signal transduction machinery.