Hypercalcemia is most commonly associated with primary hyperparathyroidism and malignancy due to parathyroid hormone-related protein (PTHrP). Primary hyperparathyroidism is characterized by excessive secretion of parathyroid hormone in association with hypercalcemia. The modern presentation of primary hyperparathyroidism is as an asymptomatic disorder. Diagnostic tools such as bone mineral densitometry, bone histomorphometry, and the measurement of markers of bone turnover, as well as other clinical assessments, have all led to the development of guidelines to help direct decisions for parathyroid surgery or for medical management. Hypercalcemia of malignancy is often distinguishable from primary hyperparathyroidism by the presence of an obvious tumor. Primary hyperparathyroidism is excluded by the immunoradiometric assay for parathyroid hormone, which is suppressed. A number of clinical characteristics of hypercalcemia of malignancy can be explained on the basis of the tumor product, PTHrP, which directly causes hypercalcemia in many cases. Assays for PTHrP show elevated levels in patients in whom hypercalcemia is associated with the classic syndrome. Recent recognition that PTHrP is found ubiquitously in virtually all normal tissues and that it is possibly involved in a number of normal physiologic processes, apart from its pathologic role, provides an exciting basis for future research.