Hyperphosphatemia is a common complication in patients with renal insufficiency. Phosphate homeostasis is primarily dependent on the interactions of two hormones, vitamin D and parathyroid hormone (PTH), and of three organ systems, the gastrointestinal tract, the kidneys, and bone. The active vitamin D metabolite, 1,25(OH)2D3, increases intestinal phosphorus absorption and PTH decreases phosphate reabsorption by the renal tubule. 1,25(OH)2D3 stimulates phosphate deposition in the bone while PTH mobilizes phosphate from the bone. Together these hormones contribute to the relative constancy of plasma phosphate. In addition, there is evidence that phosphate balance is an important moderator of circulating 1,25(OH)2D3 concentrations. In healthy chicks, phosphate restriction stimulates the activity of la-hydroxylase enzyme in the kidney, an essential enzyme in the activation of vitamin D.1 In healthy rats, phosphate restriction increases both the plasma concentration2 and the renal synthesis of 1,25(OH)2D3.3 In healthy men, the dietary intake of phosphate exerts physiologic regulation of the serum concentration of 1,25(OH)2D3. High phosphate intake decreases while low phosphate intake increases serum 1,25(OH)2D3 concentrations.4 Renal failure adversely affects the normal homeostatic function of these hormones and organs resulting in phosphate retention. Hyperphosphatemia, in turn, can further perpetuate the pathologic interactions between these systems. The pathophysiology and clinical management of hyperphosphatemia in renal insufficiency are discussed in this chapter. In addition, the two rare conditions of tumoral calcinosis and hyperphosphatemic cortical hyperostosis related to enhanced tubular reabsorption of phosphate are addressed.