While most cases of hypercalcemia are mild, severe hypercalcemia, generally defined as calcium ≥14 mg/dL constitutes a medical emergency. Severe hypercalcemia usually requires urgent hospitalization and treatment. The mainstay of initial treatment is aggressive intravenous hydration. Diagnosis of the cause of hypercalcemia is critical as further treatment is guided by etiology of the hypercalcemia. An integral step in diagnosis is determination of parathyroid hormone (PTH) level as treatment of PTH-dependent versus non-PTH-dependent hypercalcemia warrants different modes of investigation and treatment. The most common cause of hypercalcemia is PTH-dependent, that is, primary hyperparathyroidism. The most common cause of non-PTH-dependent hypercalcemia, and the second most common etiology overall, is hypercalcemia of malignancy. Calcium alkali syndrome is next most common etiology and must always be considered in non-PTH hypercalcemia. The focus of this chapter is on the presentation, etiology, and treatment of severe hypercalcemia.