Changes in the extracellular concentration of inorganic phosphate (Pi) modulate cellular function in a physiologically relevant manner. Pi-induced changes in the renal, gastrointestinal, and skeletal handling of Pi ions all contribute to the maintenance of a normal extracellular Pi concentration, although the mechanisms producing these effects are uncertain. In addition, in simpler organisms, Pi concentration in the extracellular environment is low and transport of Pi is an essential mechanism. Little is known about how external Pi concentrations are sensed or what role phosphate uptake has in Pi sensing. The sensing of Pi by mammalian cells and simpler organisms is the focus of this review.