Klotho was originally identified when a random insertional mutation disrupting the mouse gene caused an abnormal phenotype with accelerated aging and shortened lifespan. Klotho appears to play an important role in the renal handling of calcium and phosphate, in part by interacting with the FGF23 signaling system. In general, klotho tends to decrease phosphate retention and 1,25-dihydroxyvitamin D3 synthesis. It directly stimulates calcium reabsorption in the kidney and tends to increases serum calcium, but may have opposite indirect effects related to the changes in vitamin D metabolism. Klotho may also influence the response of the parathyroids to hypocalcemia and may interact with other biological systems, including Wnt, OPG/RANKL, insulin/IGF-I, and sex steroids. The actual relevance of klotho in human physiology has been recently illustrated by the identification of some rare patients with loss-of-function and gain-of-function mutations of the Klotho gene. Several studies also suggest that certain polymorphisms of the gene may influence human aging and the development of age-related diseases, such as arteriosclerosis or osteoporosis, but further investigations are needed to elucidate their true importance.