The hypercalcemia of malignancy is mediated by complex and heterogeneous mechanisms. Once thought of as a simple paraneoplastic syndrome mediated by the effects of tumor production of PTH, it is now clear that multiple mechanisms are involved and that these mechanisms involve abnormalities in calcium transport in bone, kidney, and gut. Calcium homeostasis in normal individuals is complex and tightly regulated. Although much has been learned over the last 20 years about the effects of individual hormones on target organs, much remains to be understood about how these hormonal systems interact to control extracellular fluid calcium. Future studies on disturbances in calcium homeostasis, such as that occurring in association with malignant disease, should do much to clarify how these complex hormonal mechanisms function in the normal individual.