Human phosphate homeostasis is regulated at the level of intestinal absorption of phosphate from the diet, release of phosphate through bone resorption, and renal phosphate excretion, and involves the actions of parathyroid hormone, 1,25-dihydroxy-vitamin D, and fibroblast growth factor 23 to maintain circulating phosphate levels within a narrow normal range, which is essential for numerous cellular functions, for the growth of tissues and for bone mineralization. Prokaryotic and single cellular eukaryotic organisms such as bacteria and yeast "sense" ambient phosphate with a multi-protein complex located in their plasma membrane, which modulates the expression of genes important for phosphate uptake and metabolism (pho pathway). Database searches based on amino acid sequence conservation alone have been unable to identify metazoan orthologs of the bacterial and yeast phosphate sensors. Thus, little is known about how human and other metazoan cells sense inorganic phosphate to regulate the effects of phosphate on cell metabolism ("metabolic" sensing) or to regulate the levels of extracellular phosphate through feedback system(s) ("endocrine" sensing). Whether the "metabolic" and the "endocrine" sensor use the same or different signal transduction cascades is unknown. This article will review the bacterial and yeast phosphate sensors, and then discuss what is currently known about the metabolic and endocrine effects of phosphate in multicellular organisms and human beings.