An increase in plasma calcium concentration is always the consequence of at least one of the following events: an increase in the net calcium input in extracellular fluid, a decrease in glomerular filtration rate, and an increase in the tubular reabsorption of the filtered calcium. In parathyroid hormone-related hypercalcemia, that is typically stable with time, the main determinant is the rise in parathyroid hormone-induced tubular calcium reabsorption. By contrast, in parathyroid hormone-independent hypercalcemia, usually steadily progressive (the main cause being hypercalcemia of cancer), the primary event is almost always a rapid increase in the net calcium input in extracellular fluid. The attendant hypercalcemia is commonly poorly tolerated and induces a renal sodium leak and a decrease in extracellular fluid volume. The latter leads to a fall in glomerular filtration rate and a rise in tubular calcium reabsorption which, in turn, worsen hypercalcemia. Treatment includes a reexpansion of extracellular fluid volume and the inhibition of bone calcium release.