Neoplasms of the parathyroid glands are uncommon in all species of laboratory and domestic animals, but occur in low incidence in rats, Syrian hamsters, and dogs and rarely in mice. Proliferative lesions of the parathyroid gland include hyperplasia (diffuse and focal), adenomas, and carcinomas. The tumors may be functional or nonfunctional. Trophic atrophy of remaining parathyroid tissue is present around functional tumors. Humoral hypercalcemia of malignancy (HHM) is a syndrome that occurs in human and animal patients with certain malignant neoplasms and is characterized by hypercalcemia, hypophosphatemia, and increased osteoclastic bone resorption. The syndrome is thought to be due to the release of parathyroid hormone (PTH)-like factors by the tumor cells which bind to PTH receptors in bone and kidney and result in the clinical manifestations of HHM. Parathyroid hormone-related protein (PTHrP) is a newly purified and sequenced protein which originated from human tumors associated with HHM. PTHrP has been shown to stimulate in vitro and in vivo effects similar to PTH-like proteins isolated from tumors associated with HHM. Well characterized animal models of HHM include a rat Leydig cell tumor line (Rice-500), the rat Walker mammary carcinosarcoma, and the canine apocrine adenocarcinoma. All 3 models have been found to contain 3 biologic activities which are thought to be important in the pathogenesis of HHM, viz., in vitro bone resorbing activity, adenylate cyclase-stimulating activity of bone and kidney cells, and transforming growth factor activity. The first 2 activities are due to PTH-like proteins which are able to compete for binding to the PTH receptor. The complete spectrum of functional disturbances in patients with HHM may be the result of the combined effects of a PTH-like protein (i.e., PTHrP) and transforming growth factors.