Acute hypercalcemia is a life-threatening rather rare condition. This condition may represent an acute decompensation of a pre-existing hypercalcemia, or may be acute at the first instance of the electrolyte disturbance. Hypercalcemic patients can present with a broad spectrum of symptoms, but most of them are mild and non-specific. Hypercalcemia affects a group of organs, which are considered together as a syndrome. The supportive care and ABC assessment are the first step to preserve vital functions. Severity index criteria should be considered at admission: severe dehydratation, mental status alteration, renal impairment, cardiac arrhythmias, ionized calcium level, nausea or vomiting, low social level. The neurological status and the main parameters (arterial blood pressure, cardiac pulses, oxygen saturation, temperature) must be monitored in all patients. Five keystones in the treatment of the hypercalcemic crisis should be considered: (1) Restore normovolemia to prevent renal impairment, (2) Restore renal function and enhance renal excretion of calcium, (3) Dialysis, (4) Inhibit osteoclastic bone resorption, and (5) Reduce intestinal calcium absorption. Currently, bisphosphonates are the drugs of choice in most of the patients after adequate hydration, while non-bisphosphonates drugs, such as calcitonin, gallium nitrate and mithramycin, are now rarely used. It is pivotal to recognize and treat the disease, according to evidence-based guidelines. At the same time, a short diagnostic program should be started to focus to the appropriate treatment of the underlying disease.