Humoral hypercalcemia of malignancy is a common cause of malignancy-associated hypercalcemia. This syndrome is caused by the elaboration of a tumor-derived factor or factors that induce intense bone resorption and increased renal tubular calcium reabsorption. Recently, the PTHrP has been isolated from tumors associated with HHM, and a single copy gene directing its synthesis has been identified on human chromosome 12. Analysis of mRNA from tumor-derived tissue suggests a complex pattern of hybridizing transcripts, implicating alternative processing of this gene. However, the circulating form or forms of the protein have yet to be determined. Synthetic amino-terminal polypeptides of PTHrP in vivo and in vitro reproduce all of the essential features of HHM. Preliminary studies suggest that neutralizing antisera to this protein reverse the hypercalcemia in experimental models for HHM. Thus, it appears likely that this protein has a central pathogenic role in HHM. The development of antisera to this protein will aid in the detection and diagnosis of malignancy-associated hypercalcemia. Antagonists to this molecule may be helpful in treating this disorder.