Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal boneYparathyroidYkidney axis, which is modulated by 1, 25 (oh) 2Yvitamin D (1, 25 (oh) 2D), dietary and circulating phosphate and possibly Pth. FGF23 was discovered as the humoral factor in tumors that causes hypophosphatemia and osteomalacia and through the identification of a mutant form of FGF23 that leads to autosomal dominant hypophosphatemic rickets (aDhr), a rare genetic disorder. FGF23 appears to be mainly secreted by osteocytes where its expression is upYregulated by 1, 25 (oh) 2D and probably by increased serum phosphate levels. Its synthesis and secretion is reduced through yet unknown mechanisms that involve the phosphateYregulating gene with homologies to endopeptidases on the x chromosome (PhEx), dentin matrix protein 1 (DmP1) and ectoYnucleotide pyrophosphatase/phosphodiesterase 1 (EnPP1). Consequently, lossYofYfunction mutations in these genes underlie hypophosphatemic disorders that are either xYlinked or autosomal recessive. Impaired oYglycosylation of FGF23 due to the lack of UDPYnYacetylYalphaYDYgalactosamine: polypeptide nYacetylgalactosaminylYtransferase 3 (Galnt3) or due to certain homozygous FGF23 mutations results in reduced secretion of intact FGF23 and leads to familial hyperphosphatemic tumoral calcinosis. FGF23 acts through FGFYreceptors and the coreceptor Klotho to reduce 1, 25 (oh) 2D synthesis in the kidney and probably the synthesis of parathyroid hormone (Pth) by the parathyroid glands. It furthermore synergizes with Pth to increase renal phosphate excretion by reducing expression of the sodiumYphosphate cotransporters naPiYIIa and naPiYIIc in the proximal tubules. lossYofYfunction mutations in these two transporters lead to autosomal recessive Fanconi syndrome or to hereditary hypophosphatemic rickets with hypercalciuria, respectively.