It has been assumed that the parathyroids control the level of blood calcium by a feedback mechanism whereby hypocalcemia stimulates parathormone production while hypercalcemia inhibits it. In the following experiments we have found that this explanation is too simple and that there are, in fact, 2 hormones from the parathyroid involved—parathormone, released by hypocalcemia, and a hypocalcemic factor, calcitonin, which is released by hypercalcemia. In studies on fasted anesthetized dogs, perfusion of the isolated thyroid-parathyroid glands with high calcium blood (12 mg per 100 ml) caused an immediate fall in systemic blood calcium, even in the presence of intact thyroid and parathyroid glands on the opposite side. Hypercalcemic perfusion of the thyroid gland alone was without effect. The fall in plasma calcium resulting from parathyroid hypercalcemia was significantly sooner and greater than that following total surgical thyroparathyroidectomy. This difference in response was even more striking after a period during which parathormone production had been stimulated by perfusing the parathyroids with low calcium blood. In such animals, parathyroidectomy was followed by a sustained rise in plasma calcium, while high calcium perfusion of the glands resulted in the usual prompt fall. This latter effect cannot be explained on the basis of inhibited parathormone production for, if this were the case, parathyroidectomy should have produced the same effect. The evidence indicates that hypercalcemia causes the release of a hypocalcemic factor from the parathyroids that lowers the blood calcium and antagonizes the effect of parathormone. This factor has been demonstrated in hypercalcemic perfusates of the parathyroids, in commercial parathyroid extracts and in preparations of beef parathyroid glands that were free of parathormone activity. When normocalcemic blood was perfused through the glands, no activity could be demonstrated in the perfusate. When preparations containing the hypocalcemic factor were injected iv into assay dogs, the maximum fall in plasma calcium occurred 20 minutes later. If no parathormone activity was present, the plasma calcium returned to the control level within an hour. Repeated injections of active perfusate at 20-minute intervals resulted in a progressive lowering of the plasma calcium. The hypocalcemic factor prevents the hypercalcemia that otherwise would result from excess parathormone production. Following parathyroidectomy, this functional control is lost. We have proposed that this new hormone be named “calcitonin,” since it is involved in the regulation of the normal calcium level or “tone” in body fluids. With parathormone, it provides a dual hormonal feedback mechanism that accounts for the precise control of the level of plasma calcium in the normal animal.