Hypophosphatemia is commonly missed due to nonspecific signs and symptoms, but it causes considerable morbidity and in some cases contributes to mortality. Three primary mechanisms of hypophosphatemia exist: increased renal excretion, decreased intestinal absorption, and shifts from the extracellular to intracellular compartments. Renal hypophosphatemia can be further divided into fibroblast growth factor 23-mediated or non-fibroblast growth factor 23-mediated causes. Proper diagnosis requires a thorough medication history, family history, physical examination, and assessment of renal tubular phosphate handling to identify the cause. During the past decade, our understanding of phosphate metabolism has grown greatly through the study of rare disorders of phosphate homeostasis. Treatment of hypophosphatemia depends on the underlying disorder and requires close biochemical monitoring. This article illustrates an approach to the hypophosphatemic patient and discusses normal phosphate metabolism.