Humoral hypercalcemia of malignancy (HHM) is a common paraneoplastic syndrome mediated by tumor-derived parathyroid hormone-related peptide (PTHRP), which bears structural and functional similarities to PTH. Thus the clinical features of HHM are very similar to those of primary hyperparathyroidism (1 degree HPT), a prototype of humoral hypercalcemia caused by PTH. On the other hand, HHM syndrome differs from 1 degree HPT in several aspects, including serum 1,25(OH)2D levels, acid-base balance, and bone remodeling process, the reason of which remains largely unknown. We approached these questions using a unique animal model of HHM, nude rats implanted with PTHRP-overproducing human carcinomas. In this review we will summarize the results and discuss the implications in understanding the disease mechanism.