The critical role of phosphate (Pi) in countless biological processes requires the ability to control its concentration both intracellularly and extracellularly. At the body level, this concentration is finely regulated by numerous hormones, primarily parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). While this control of the body’s Pi homeostasis is now well documented, knowledge of the mechanisms that allow the cell and the body to detect extracellular Pi variations is much less known. These systems are well described in bacteria, yeasts and plants, but as will be discussed in this review, knowledge obtained from these organisms is not entirely relevant to the requirements of Pi biology in mammals. In this review, we present the latest findings on extracellular Pi sensing in mammals, and describe the mammalian Pi sensors identified to date, such as SLC20A1 (PIT1)/SLC20A2 (PIT2) heterodimers and the calcium-sensing receptor (CaSR). While there are many questions remaining to be resolved, a clarification of the Pi sensing mechanisms in mammals is critical to understanding the deregulation of Pi balance in certain life-threatening disease states, such as end-stage renal disease and associated vascular calcifications, and to proposing relevant therapeutic approaches.