Alterations of calcium homeostasis leading to hypercalcemia can occur at three different levels: the bone (increased osteoclast activity), kidney (increased 25(OH)D hydroxylation and/or reduced calcium tubular excretion), and intestine (enhanced absorption of calcium), or a combination of them. The prevalence of hypercalcemia in general population accounts for 1–2%, and it is estimated that approximately 90% of cases are caused by primary hyperparathyroidism or malignancy, the latter occurring between 7 and 30% of cancer patients. Two major mechanisms are responsible for the development of malignancy-related hypercalcemia (MRH): (i) humoral, mediated by elevated circulating substances released by cancer cells, able to activate osteoclasts, with subsequent increased bone resorption and possibly renal reabsorption of calcium, and (ii) osteolytic, due to the direct local action of cancer cells, which can occur because bone is a common site of metastases. Solid tumors more frequently associated with humoral hypercalcemia are breast and squamous cell carcinomas, while a large proportion of patients with advanced prostate cancer may develop osteolytic metastases. The management of MRH depends on both the severity of clinical manifestations (acute vs. chronic hypercalcemia) and serum calcium levels. The first steps of treatment are to increase circulating volume, enhance calcium excretion, and restore renal function. The aim of further therapies is mainly to reduce osteoclastic activity and subsequent bone resorption, using bisphosphonates or denosumab, which currently represent the mainstay of treatment of MRH. Denosumab seems to be superior to zoledronic acid in reducing the risk of skeletal-related events and does not demonstrate renal toxicity compared to bisphosphonates.