Even one century after its discovery, there are still many gaps in the understanding of the vitamin D endocrine system. Inactivation of the vitamin D receptor (VDR) or the enzymes metabolizing its ligand (especially Cyp27bl) in mice has clearly demonstrated that the active form of vitamin D [1,25(OH)2D] is essential to stimulate calcium absorption in the gut during normal/low calcium intake, and as a consequence, that 1,25(OH)2D is required to maintain normal serum calcium, bone and growth plate homeostasis. These findings have resulted in clear clinical guidelines for the treatment of vitamin D-related bone diseases of infants, children and adults. Tissue-specific VDR or Cyp27b1 deletion in mice has also proven to be useful to define the precise role of 1,25(OH)2D action in cells belonging to the intestine, bone, growth plate and also to many non-classical target tissues. Indeed, experimental findings show that 1,25(OH)2D has numerous extraskeletal effects, and observational studies in man demonstrate that disturbances in the vitamin D pathway are associated with major human diseases such as cancer, infections, autoimmune diseases, cardiovascular and metabolic diseases, muscle function, reproduction and neurocognitive disorders. We will compare the findings in VDR- and Cyp27bi-null mice with findings in man to elucidate what is presently understood of the vitamin D endocrine system and to identify the still outstanding questions.