Hypercalcemia may be seen in a variety of clinical settings and often requires intensive management when serum calcium levels are dramatically elevated. All of the many etiologies of mild hypercalcemia can lead to severe hypercalcemia. Knowledge of the physiologic mechanisms involved in maintaining normocalcemia and basic pathophysiology is essential for making a timely diagnosis and hence prompt institution of etiology-specific therapy. The development of new medications and critical reviews of traditional therapies have changed the treatment paradigm for severe hypercalcemia, calling for a more limited role for aggressive isotonic fluid administration and furosemide and an expanded role for calcitonin and the bisphosphonates. Experimental therapies such as denosumab show promise.