Recent studies in mice using genetic approaches have shed new light on the physiological effects of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and the vitamin D receptor (VDR) in skeletal and mineral homeostasis, and on their interaction with calcium. These studies in mice with targeted deletion of the 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha(OH)ase), and of the VDR or of double mutants, have shown the discrete effects of calcium in inhibiting parathyroid hormone secretion and in enhancing bone mineralization, but overlapping effects of calcium and 1,25(OH)(2)D on inhibiting parathyroid growth and on normal development of the cartilaginous growth plate. The 1,25(OH)(2)D/VDR system is essential, however, in enhancing intestinal calcium absorption and in optimally increasing osteoclastic activation. In addition, the 1,25(OH)(2)D/VDR system has important anabolic effects on bone, thus defining a dual role for this system in bone turnover. These studies are revealing functions of the vitamin D/VDR system which have relevance for new concepts of the pathophysiology of renal bone disease and, in particular, of the adynamic bone disorder, and for the development of new analogs of the active form of vitamin D, which have less calcemic activity and greater skeletal anabolic effects.