The analysis of mice that lack systemically the actions of the active form of vitamin D, 1,25(OH)2 D, has shown that 1,25(OH)2 D is an essential regulator of calcium homeostasis and that its actions are aimed at maintaining serum calcium levels within narrow limits. Especially the stimulation of intestinal calcium transport by 1,25(OH)2 D is important for calcium and bone homeostasis. The involved transporters are however still elusive. The targeted deletion of 1,25(OH)2 D action in chondrocytes has provided compelling evidence for a paracrine control of bone development and endocrine regulation of phosphate homeostasis by 1,25(OH)2 D. Targeting vitamin D receptor (VDR) function in other tissues will further enhance our understanding of the cell-type specific action of 1,25(OH)2 D. In this review, we will discuss the current understanding and remaining questions concerning the calcemic actions of 1,25(OH)2 D in the intestine, kidney and bone, with special focus on the evidence obtained by the use of transgenic mouse models.