Small decreases in serum Ca²⁺and more prolonged increases in serum phosphate (P_i) stimulate the parathyroid (PT) to secrete parathyroid hormone (PTH), and 1,25(OH)₂D₃decreases PTH synthesis and secretion. A prolonged decrease in serum Ca²⁺and 1,25(OH)₂D₃, or increase in serum P_i, such as in patients with chronic renal failure, leads to the appropriate 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. Low serum Ca²⁺leads to an increase in PTH secretion, PTH mRNA stability, and PT cell proliferation. P_ialso regulates the PT in a similar manner. The effect of Ca²⁺on the PT is mediated by a membrane Ca²⁺receptor. 1,25(OH)₂D₃decreases PTH gene transcription. Ca²⁺and P_iregulate the PTH gene posttranscriptionally by regulating the binding of PT cytosolic proteins, trans factors, to a defined cissequence in the PTH mRNA 3′-untranslated region, thereby determining the stability of the transcript. PT trans factors and cis elements have been defined.