Calcium and phosphate are essential to many vital physiological processes, making the maintenance of their homeostasis crucial for survival. A tightly controlled balance of calcium and phosphorus is maintained by hormonal control of transport in the intestine, bone, and kidney. The kidneys participate by modulating calcium and phosphate reabsorption from the glomerular filtrate according to the body needs. This process is mediated by ion transporters. Besides the classical endocrine factors (i.e., PTH and vitamin D metabolites), new factors have been identified that are involved in maintaining calcium and primarily phosphate balance. Fibroblast growth factor-23 (FGF23) regulates urinary phosphate excretion by interacting with FGF receptors. Klotho, a transmembrane protein, facilitates this interaction, with the result of reducing phosphate reabsorption by the kidney leading to hypophosphatemia. More recently, dental matrix protein-1, an osteocyte product, has been shown to participate in FGF23-mediated regulation of phosphorus homeostasis. Transgenic mouse models have been of great value in the elucidation of Klotho and FGF23 function. This review highlights current knowledge into calcium and phosphate homeostasis in health and disease.