Publisher Summary This chapter focuses on current understanding of the physiology and mechanism of action of these polypeptides. Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are major factors that regulate skeletal physiology and mineral homeostasis. However, the major physiological function of PTHrP is to act as a local factor that controls the development, morphogenesis, and function of a variety of tissues, including those involved in skeletal and mineral homeostasis. They are also related structurally and produce their major physiological effects by activating a common receptor, the PTH/PTHrP (or PTH1) receptor. Studies on the PTH/PTHrP receptor demonstrated a prominent role for GTP and its analogues in regulating ligand–receptor affinity and signaling, suggesting that this receptor couples to GTP-binding (G) proteins. The cloning of the cDNA encoding the PTH/PTHrP receptor revealed a predicted protein sequence containing seven putative membrane-spanning domains, a topology characteristic of members of the GPCR superfamily. In the case of the PTH/PTHrP receptor, the major G-proteins that can be activated are Gs and Gq. Activation of Gs leads to increased adenylyl cyclase activity, resulting in increased cellular levels of cyclic AMP and activation of PK-A. Activation of Gq results in the stimulation of phospholipase C, resulting in the mobilization of intracellular calcium and activation of PK-C. A physiological role for PTHrP fragments is suggested by studies of placental calcium transport. The fetal parathyroid gland is required to maintain the normal positive maternal–fetal calcium gradient, at least in sheep. This gradient can be restored in parathyroidectomized fetuses by the administration of midregion fragments of PTHrP, but not by PTH or by amino-terminal PTHrP fragments. This effect must therefore be initiated by a receptor distinct from the classical PTH/PTHrP receptor.