Calcium and phosphorus homeostasis relies on a complex, tightly regulated system involving many ions and hormones. The regulation of calcium and phosphorus is controlled by the actions of these ions and hormones on the intestine, kidneys and bone. Disturbances in the serum level of calcium and/or phosphorus can lead to significant pathology, including kidney stones and bone disease. In addition to parathyroid hormone and vitamin D, recently identified factors such as fibroblast growth factors and klotho play an important role in maintaining mineral ion homeostasis. The identification of subfamily V transient receptor potential cation channels (TRPV channels), Na/Pi cotransporters, the vitamin D receptor and the calcium-sensing receptor have further advanced our understanding of this complex physiology. In this review we discuss the current understanding of the relationships between the ions, hormones, and transporters that maintain calcium and phosphorus homeostasis.