Inorganic phosphate (P(i)) is required for energy metabolism, nucleic acid synthesis, bone mineralization, and cell signaling. The activity of cell-surface sodium-phosphate (Na(+)-P(i)) cotransporters mediates the uptake of P(i) from the extracellular environment. Na(+)-P(i) cotransporters and organ-specific P(i) absorptive processes are regulated by peptide and sterol hormones, such as parathyroid hormone (PTH) and 1alpha,25-dihydroxyvitamin D (1alpha,25(OH)(2)D(3)), which interact in a coordinated fashion to regulate P(i) homeostasis. Recently, several phosphaturic peptides such as fibroblast growth factor-23 (FGF-23), secreted frizzled related protein-4 (sFRP-4), matrix extracellular phosphoglycoprotein, and fibroblast growth factor-7 have been demonstrated to play a pathogenic role in several hypophosphatemic disorders. By inhibiting Na(+)-P(i) transporters in renal epithelial cells, these proteins increase renal P(i) excretion, resulting in hypophosphatemia. FGF-23 and sFRP-4 inhibit 25-hydroxyvitamin D 1alpha-hydroxylase activity, reducing 1alpha,25(OH)(2)D(3) synthesis and thus intestinal P(i) absorption. This review examines the role of these factors in P(i) homeostasis in health and disease.