In vivo dynamic tests of parathyroid gland function have provided useful information about the secretory behavior of parathyroids in various clinical disorders, but the limitations of this approach must be recognized when applied to studies of parathyroid gland physiology. Set point abnormalities have been documented in vivo both in primary hyperparathyroidism and in familial hypocalciuric hypercalcemia. Such findings are consistent with in vitro results obtained in studies of dispersed parathyroid cells from patients with primary hyperparathyroidism and with recently described alteration in calcium receptor expression in patients with FHH. The assessment of parathyroid gland function in patients with end-stage renal disease presents distinct methodological problems, however, because of marked variation in the degree of parathyroid gland enlargement. Neither the four parameter model originally used to describe set point abnormalities both in vitro and in vivo or alternative approaches to the assessment of PTH secretion in vivo adequately address this important issue. Results from recent in vivo studies of patients with chronic renal failure do not support the view that the set point for calcium-regulated PTH release is abnormal in secondary hyperparathyroidism or that treatment with calcitriol lowers the set point for calcium-regulated PTH release in patients with uremic secondary hyperparathyroidism. The concept of set point disturbances has strongly influenced discussions about the pathogenesis of secondary hyperparathyroidism, and it has served as a focal point for examining the therapeutic response to calcitriol in patients with this disorder. This matter requires careful reconsideration, however, in light of recent clinical findings and the development of techniques to directly assess the molecular mechanisms responsible for regulating calcium-mediated PTH release in renal failure and other disorders of mineral metabolism. Although knowledge in this area remains limited, the extent of parathyroid hyperplasia and the role of factors that influence the development of parathyroid gland enlargement may ultimately prove to be particularly important modifiers of parathyroid gland function in chronic renal failure.