Since many patients (50% or more) with cancer and hypercalcemia do not have demonstrable bone metastases or PHPT, it has long been suspected that the cancer could be producing a parathyroid hormonelike substance. The parathyroid hormone-related protein (PTHrP) molecule has a C-terminal end and an N-terminal end like PTH; in addition, a portion of the PTHrP amino acid sequence is identical to that of PTH, although the majority of the PTHrP molecule is not. Also, it has been found that certain normal tissues can produce PTHrP (including the keratinized layer of skin epidermis, lactating breast tissue, placenta, adrenal, and a few others). PTHrP has recently been isolated and cloned, and antibodies have been obtained that react against it. Several investigators have reported results using homemade test kits, and one commercial kit is now available. Results thus far with these first-generation kits show that about 50% (range, 20%-91%) of patients with solid malignancies and hypercalcemia have increased PTHrP levels. Another 20% have bone metastases that could account for hypercalcemia without hormonal basis. It is currently thought that the other 30% may be producing some type of altered PTHrP that is not being detected by current antibodies. PTHrP assay may be useful when PTH assays fail to give expected results in patients with malignancy or give results that are borderline or slightly overlapping in nomogram areas between PHPT and tumor patients. However, PTHrP assays are not all alike and it is necessary to find a laboratory or kit that gives superior results.