Phosphate plays a key role in several biological processes. In recent years, new insights have been obtained into the regulation of the phosphate metabolism, including a growing amount of evidence suggesting that factors other than parathyroid hormone (PTH) and vitamin D are involved in maintaining the phosphate balance. A new class of phosphate-regulating factors, the so-called "phosphatonins," have been shown to be important in phosphate-wasting diseases. However, the role of the phosphatonins in the normal human homeostasis remains to be established. The incidence of hypophosphatemia in selected patient series can be more than 20%, with clinical sequelae ranging from mild to life threatening. Only when combined with phosphate depletion does hypophosphatemia become clinically significant. The factors that are involved in the phosphate homeostasis, the pathophysiology, the relevance in patient care, the clinical manifestations, and an appropriate management of phosphate depletion are discussed in this review.