Phosphorus is an essential element in skeletal development, bone mineralization, membrane composition, nucleotide structure, and cellular signaling. Phosphate, the principal form in which phosphorus is found in the body, is regulated by the complex interplay of the hormones parathyroid hormone (PTH), calcitriol (1,25[OH](2) vitamin D(3)), and fibroblast growth factor 23 (FGF23). These collectively govern bone mineralization, absorption of phosphorus by the intestine, and renal tubular reabsorption of phosphate. The skeleton is the major storage pool for phosphate and the principal production site for FGF23, a major phosphate regulatory hormone. Recent advances in understanding the molecular basis of disorders of phosphate metabolism have revealed new phosphate-regulatory hormones and provided insight into how these regulators may interface with previously known phosphate-regulatory pathways. Here we outline the current knowledge about the regulation of normal phosphate homeostasis and present a review of the molecular basis of disorders of phosphate homeostasis.