Small decreases in serum calcium (Ca(2+)) and more-prolonged increases in serum phosphate (Pi) stimulate the parathyroid (PT) to secrete parathyroid hormone (PTH). 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2) D(3)] decreases PTH synthesis and secretion. The prolonged decrease in serum Ca(2+) and 1,25(OH)(2) D(3), or increase in serum Pi, observed in patients with chronic renal failure leads to a secondary increase in serum PTH. This secondary hyperparathyroidism involves increases in PTH gene expression, synthesis, and secretion and, if chronic, to proliferation of the PT cells. A low serum Ca(2+) leads to an increase in PTH secretion, PTH mRNA stability, and PT cell proliferation. Pi also regulates the PT in a similar manner. The effect of Ca(2+) on the PT is mediated by a membrane Ca(2+) receptor. 1,25(OH)(2) D(3) decreases PTH gene transcription. Ca(2+) and Pi regulate the PTH gene post transcriptionally by regulating the binding of PT cytosolic proteins, trans factors, to a defined cis sequence in the PTH mRNA 3'-untranslated region, thereby determining the stability of the transcript. The PT trans factors and cis elements have been defined.