Vitamin D has a key role in stimulating calcium absorption from the gut and promoting skeletal health, as well as many other important physiological functions. Vitamin D is produced in the skin. It is subsequently metabolized to its hormonally active form, 1,25-dihydroxyvitamin D (1,25(OH)₂D), by the 1-hydroxylase and catabolized by the 24-hydroxylase. In this Review, we pay special attention to the effect of mutations in these enzymes and their clinical manifestations. We then discuss the role of vitamin D binding protein in transporting vitamin D and its metabolites from their source to their targets, the free hormone hypothesis for cell entry and HSP70 for intracellular transport. This is followed by discussion of the vitamin D receptor (VDR) that mediates the cellular actions of 1,25(OH)₂D. Cell-specific recruitment of co-regulatory complexes by liganded VDR leads to changes in gene expression that result in distinct physiological actions by 1,25(OH)₂D, which are disrupted by mutations in the VDR. We then discuss the epidermis and hair follicle, to provide a non-skeletal example of a tissue that expresses VDR that not only makes vitamin D but also can metabolize it to its hormonally active form. This enables vitamin D to regulate epidermal differentiation and hair follicle cycling and, in so doing, to promote barrier function, wound healing and hair growth, while limiting cancer development.