Phosphate homeostasis in humans is a complex phenomenon involving the interplay of several different organs and circulating hormones. Among the latter, parathyroid hormone (PTh), and vitamin D3 (Vit D3) were thought to be the main regulators of serum phosphate concentration since they mediated the intestinal, renal and bone responses that follow fluctuations in serum phosphate levels. The study of three rare disorders - tumor-induced osteomalacia (TIo), autosomal dominant hypophosphatemic rickets (ADhr) and X-linked hypophosphatemic rickets (XLh) - has offered a completely new insight into phosphate metabolism by unraveling the role of a group of peptides that can directly affect serum phosphate concentration by increasing urinary phosphate excretion. fibroblast growth factor-23 (fGf-23) is the most extensively studied ''phosphatonin''. The production, mechanism of action, effects in various target tissues, and its role in common clinical disorders are the focus of this review.