Calcitonin, a potent hypocalcemic hormone produced by the C-cells of the thyroid, was first discovered by Harold Copp in 1962. The physiological significance of calcitonin has been questioned, but recent studies using genetically modified mouse models have uncovered additional actions of calcitonin acting through its receptor (CTR) that are of particular significance to the regulation of bone and calcium homeostasis. Mice in which the CTR is deleted in osteoclasts are more susceptible to induced hypercalcemia and exogenous calcitonin is able to lower serum calcium in younger animals. These data are consistent with the hypothesis that calcitonin can regulate serum calcium by inhibiting the efflux of calcium from bone, and that this action is most important when bone turnover is high. Calcitonin has also been implicated in protecting the skeleton from excessive loss of bone mineral during times of high calcium demand, such as lactation. This action may be linked to an intriguing and as yet unexplained observation that calcitonin inhibits bone formation, because deletion of the CTR leads to increased bone formation. We propose several mechanisms by which calcitonin could protect the skeleton by regulating bone turnover, acting within the bone and/or centrally. A new more holistic notion of the physiological role of calcitonin in bone and calcium homeostasis is required and we have highlighted some important knowledge gaps so that future calcitonin research will help to achieve such an understanding. © 2013 American Society for Bone and Mineral Research.