The genesis of hyperparathyroidism in uremia has turned out to be quite complex, involving low calcitriol, low ionized calcium, and possibly direct effects of high phosphate as well as the action of local factors and modifier genes determining the hyperplastic response of the gland. Growth is initially polyclonal and later monoclonal. In addition, the response of target tissues to parathyroid hormone (PTH) is attenuated ("PTH resistance"), and this may be due, at least in part, to diminished phenotypic expression of PTH receptors. In a series of elegant studies, it has been shown that PTH acts not only on the classical target organs of calcium homeostasis (ie, bone and kidney), but also on nonclassical. The role of PTH excess in the genesis of several features of the uremic syndrome, for example muscle dysfunction, cardiomyopathy, leukocyte and T-cell dysfunction or insulin secretion by pancreatic islet cells, has been established. These studies have borne out the prediction that PTH is a "uremic toxin."