Understanding the physiological regulation of mineral ion metabolism is essential for determining the pathomechanisms of skeletal, vascular, and renal diseases associated with an abnormal regulation of calcium and phosphate homeostasis. Normal calcium and phosphate balance is delicately maintained by endocrine factors that coordinate to influence the functions of the intestine, bone, parathyroid gland, and kidney. Under physiological conditions, the kidneys play an important role in maintaining the normal mineral ion balance by fine-tuning the amount of urinary excretion of calcium and phosphate according to the body's needs. Fibroblast growth factor 23 (FGF23) regulates urinary phosphate excretion to maintain systemic phosphate homeostasis. The exact mode of action of the phosphaturic effects of FGF23 is not fully understood and is an intense area of research. Studies suggest, however, that FGF23, by interacting with FGF receptors, can initiate downstream signaling events and that Klotho, a transmembrane protein, facilitates the interaction of FGF23 with its receptor. FGF23 can inhibit the activities of 1 alpha-hydroxylase and sodium-phosphate cotransporter in the kidney to influence the overall systemic phosphate balance. In this article, we briefly summarize how FGF23 might coordinately regulate systemic phosphate homeostasis and how Klotho is involved in such regulation.