Identification of vitamin D as a potent antirachitic factor almost a century ago prompted investigations aimed at addressing its mechanism of action and key target tissues. Studies in vitamin D deficiency models and in kindreds with impaired hormone activation and function were critical in identifying key steps in the vitamin D signaling pathway. Studies in humans with vitamin D receptor (VDR) mutations provided a tremendous amount of information regarding the role of this receptor in calcium and skeletal homeostasis. The availability of mouse models of VDR ablation provided an important tool for detailed molecular analyses of the pathophysiologic basis for the skeletal, parathyroid and cutaneous phenotypes observed in mice and humans with impaired VDR function. These investigations revealed that a critical action of the liganded receptor is the promotion of intestinal calcium absorption. Bypassing this defect by dietary or transgenic rescue prevents the severe skeletal phenotype of the VDR ablated mice, as well as the development of hyperparathyroidism. In contrast, intestine specific ablation of the receptor results in marked skeletal pathology. Like their human counterparts, VDR knockout mice develop alopecia. Studies in these mice demonstrated that the actions of the VDR required for cyclical regeneration of the hair follicle and prevention of alopecia were shown independent of 1,25-dihydroxyvitamin D demonstrating that the unliganded receptor has an important role in the cutaneous homeostasis.