It is now 20 years since the tumor-associated factor parathyroid hormone-related peptide was identified. Since then, there have been significant changes in the understanding of the hypercalcemic syndromes associated with malignancy and with the role of this peptide in normal physiology as well as this specialized pathologic setting. Parathyroid hormone-related peptide has become a useful diagnostic tool in the differential diagnosis of hypercalcemia, and approaches to inhibit its expression or its effects by malignant cells hold promise for treating the hypercalcemia and osteolysis associated with some cancers.