In the three endocrine/neuroendocrine systems discussed, there are demonstrable declines in post-maturational responsiveness. Parathyroid hormone stimulation of 1,25-dihydroxyvitamin D production declines with age in the kidney as does calcium absorption in the intestine. Chronotropic and inotropic responsiveness to beta-adrenergic agonists decreases with age in the myocardium, and performance on passive avoidance tasks related to memory dysfunction declines with age in rodents. In each case there is a corresponding decrease in receptor activation with age. Parathyroid hormone receptors are less able to activate adenylate cyclase in older rat kidneys; beta-adrenergic receptors have reduced density in some tissues, demonstrate reduced agonist affinity (are uncoupled), and are less able to activate adenylate cyclase in most tissues with age; and muscarinic receptors demonstrate mixed agonist affinity (are uncoupled) with age in rat hippocampal cells. This reduction in receptor activation can be attributed to desensitization to increased agonist concentrations. Parathyroid hormone receptor activation is restored by parathyroidectomy, beta-adrenergic agonists no longer desensitize in older animals, and muscarinic receptors from senescent rats pharmacologically mimic desensitized receptors. However, desensitization of receptor activation cannot fully account for the reduced hormonal responsiveness in any of these systems. Parathyroidectomy does not restore 1,25-dihydroxyvitamin D production or intestinal calcium absorption. There are age-related post receptor deficits in beta-adrenergic pathway that are not mediated by changes in serum catecholamines. In conclusion, there are significant changes in receptor and post-receptor biochemistry with age. The overall decreases in hormonal responsiveness are not due to a single biochemical defect in the system and are probably multiple in nature.