Malignancy is the most frequent cause of hypercalcemia in hospitalized patients. The pathophysiology of hypercalcemia of malignancy (HM) is complex. Increased bone resorption is involved in most cases caused either by extensive local bone destruction or by humoral factors. Tumor extracts from patients with humoral hypercalcemia of malignancy (HHM) often contain PTH-like bioactivity. Recently, cDNAs coding for a PTH-related protein (PTH-rP) has been cloned. The N-terminal amino acid sequence of this protein shows a considerable homology with human PTH. However, other bone resorbing factors including prostaglandins, transforming growth factors, colony stimulating factors, leucocyte cytokines and 1,25-dihydroxyvitamin D may be involved in different types of malignancy. HM is usually progressive with troublesome symptoms and a high mortality. Several treatment alternatives are available including rehydration, bisphosphonates, calcitonin, plicamycin, phosphate, and glucocorticoids. Others are under investigation. Treatment should be individualized taking into account the pathophysiological mechanisms involved, the extent of hypercalcemia and renal failure, and the prognosis related to the malignant disease.