Hypercalcemia is commonly encountered in clinical practice, and mild hypercalcemia is usually identified in asymptomatic patients in the outpatient population. Severe hypercalcemia requires medical admission to hospital. The pathophysiology leading to hypercalcemia includes increased bone resorption as well as enhanced renal calcium reabsorption and/or increased gastrointestinal absorption of calcium. The presence of hypercalcemia requires confirmation followed by evaluation to determine if it is parathyroid hormone (PTH) dependent or PTH independent in etiology. The most common causes of hypercalcemia accounting for 80–90% of the cases are primary hyperparathyroidism (PHPT) which often presents in a healthy outpatient population and malignancy-associated hypercalcemia which usually presents with significant hypercalcemia requiring admission to hospital. Less common causes of hypercalcemia include granulomatous disease, drugs, adrenal insufficiency, hyperthyroidism, and benign tumors. This chapter reviews the causes of hypercalcemia as well as the clinical manifestations and provides a diagnostic and therapeutic approach of hypercalcemia today.