PARATHYROID hormone-related protein (PTHrP) bioactivity was identified in 1983 in tumors associated with humoral hypercalcemia of malignancy (HHM). The N-terminal amino acid and complementary DNA (cDNA) sequences were identified in 1987. The search for the causative agent of HHM was fueled by the frequency with which HHM occurs, by the severe complications of hypercalcemia (coma, renal failure, death), and by the identification in clinical and laboratory studies of a novel calcium-regulating hormone that could be postulated as the cause of HHM. It was expected at the time that this search would lead to the purification of the responsible “humor,” and that that “humor,” when identified, would prove to have some normal physiological role. It was not anticipated that the “humor” would prove to be produced by almost every type of cell in the body at some stage of development, or that the search for the novel “humor” would lead to the identification of an unusually large, complicated, and interesting family of peptide hormones.