Until recently, the action of two hormones - parathyroid hormone (PTH) and calcitriol - on three target tissues - bone, kidney, and gut - has been thought to regulate the closely linked homeostasis of calcium and phosphates. In this system, an increase in the plasma concentration of one ion often leads to a reciprocal change in the concentration of the other and PTH stimulates 1 alpha-hydroxylase activity and calcitriol synthesis in renal proximal tubular cells. A second phosphate regulation system was recently identified. It involves one or more phosphaturic hormones, called "phosphatonins", that is, circulating factors with potent phosphaturic activity. The key phosphatonin appears to be a fibroblast growth factor, known as FGF23. It is now established that FGF23 regulates not only phosphate homeostasis, but also vitamin D metabolism. In contrast to PTH, however, FGF23 inhibits rather than stimulates 1 alpha-hydroxylase activity and calcitriol synthesis.