Purpose of Review Despite the important progress made in understanding the regulation of phosphate (Pi) homeostasis over the past 20 years, the mechanisms underlying the very early step leading to the regulating cascade involving multiple hormones (PTH, vitamin D, FGF23) and organs (kidney, intestine, bone, parathyroid glands) are not deciphered. Particularly, knowledge on the Pi-sensing mechanism present within or on the surface of the cell that is able to detect changes in serum or local Pi concentrations and trigger an appropriate FGF23 synthesis/secretion is limited or absent. Recent Findings Several molecular actors have recently been involved as potential key players in Pi sensing and Pi-dependent control of FGF23 secretion. Among them, the PiT1/Slc20a1 and PiT2/Slc20a2 proteins are standing out. Summary We are just beginning to accumulate in vitro and in vivo data that will provide invaluable molecular tools to explore and understand the integrated response of the body to variations of Pi concentration.