Hypercalcemia, a complication that develops in 10% to 20% of patients with cancer, results from disruption of the normal physiologic mechanisms that closely regulate calcium homeostasis. Most patients with hypercalcemia are seriously dehydrated, and this volume depletion further compromises the kidney's ability to excrete calcium. Replenishment of extracellular fluid, restoration of intravascular volume, and maintenance of saline diuresis are the cornerstones of initial therapy. In most patients, pharmacologic inhibition of abnormally increased osteoclastic resorption is necessary to normalize serum calcium and achieve long-term control. The severity of the hypercalcemia and the patient's renal function, bone marrow reserve, and anticipated response to specific antineoplastic agents can all influence the selection of an antihypercalcemic agent. Available drugs for initial therapy include calcitonin, plicamycin, and etidronate; several additional investigational agents have shown promising efficacy in controlling hypercalcemia of malignancy. The bisphosphonates have an excellent safety profile and appear to be the agents of choice for initial and long-term management of cancer-related hypercalcemia.