Availability of immunoassays for specific regions of the parathyroid hormone (PTH) molecule allows discrimination with a high level of surety between primary hyperparathyroidism and tumoral hypercalcemic states associated with circulating PTH-like substances. Assay for intact, N-terminal PTH currently has the highest discriminant function. Prostaglandin-dependent and osteoclast-activating factor-mediated hypercalcemic states associated with neoplasia have suppressed serum PTH levels. PTH-like substances are detected by immunoassays, but in the intact, N-terminal system they are seen as normal-range or low values. The frequency with which any tumor produces only authentic PTH is very low. The serum chloride:phosphate ratio has limited clinical utility in distinguishing tumoral hypercalcemia from hyperparathyroid hypercalcemia, and measurements of nephrogenous cyclic AMP do not distinguish between the effects of circulating authentic PTH and PTH-like substances elaborated by tumors. Additional measures that, in the future, may help to distinguish between parathyroid and tumoral hypercalcemias include quantitative bone biopsy histomorphometry and in vitro bioassays for PTH activity in the separate plasma fractions, obtained by gel filtration, in which PTH and PTH-like substances are found.