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 1α,25-dihydroxyvitamin D (1α,25(OH)₂D₃), 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 1α-hydroxylase activity, reducing 1α,25(OH)₂D₃ synthesis and thus intestinal P_i absorption. This review examines the role of these factors in P_i homeostasis in health and disease.