Vitamin D is a steroid pro‐hormone, whose active metabolite binds the vitamin D receptor (VDR) which, in turn, binds to DNA sequences on target genes as a heterodimer with the retinoid‐X receptor, resulting in regulation of gene expression. The vitamin D pro‐hormone can be synthesized in the skin, in response to ultraviolet radiation; however, dietary sources have become increasingly important as a result of cultural changes over the past few centuries. Based on its initial discovery as an anti‐rachitic factor, studies of the role of vitamin D and its receptor have largely focused on the skeleton. Investigations into the pathophysiologic basis and therapeutic responses of skeletal disorders associated with impaired vitamin D action have led to the identification of the molecular pathways involved in hormone activation and regulation of gene expression by the liganded VDR. These studies have also demonstrated that the skeletal actions of the VDR and its ligand are largely redundant if normal mineral ion homeostasis can be maintained by other means. However, investigations in animal models with tissue‐specific ablation of the VDR or the enzyme required for hormone activation have demonstrated novel actions in skeletal tissues. The active vitamin D metabolite has been shown to have both paracrine and endocrine actions in other tissues as well. J. Cell. Biochem. 111: 7–13, 2010. © 2010 Wiley‐Liss, Inc.