Hypercalcemia is the most common metabolic complication of cancer. Malignancy-associated hypercalcemia (MAHC) can be divided into two syndromes, humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia (LOH), based on whether a circulating hormone or local paracrine factors mediate accelerated bone resorption. Over the past decade, studies have shown that parathyroid hormone-related protein is the cause of the HHM syndrome, and recent data suggest that this protein may also play a paracrine role in some patients with local osteolytic hypercalcemia. Study of the regulation of parathyroid hormone-related protein gene expression is beginning to shed some light on the molecular mechanisms responsible for this common clinical problem.