Age-related changes in the hormonal control of glucose homeostasis were examined in immature (5-wk-old), young adult (10-wk-old) and older adult (30 and 60-wk-old mice). In immature mice, basal plasma glucose and insulin concentrations were higher than young adult mice. Glucose tolerance was impaired in immature mice, although the plasma insulin response to glucose and other secretagogues (arginine and glucagon) was well developed, and the hypoglycaemic effect of exogenous insulin was not impaired. Glucagon and epinephrine evoked a greater acute hyperglycaemia in immature mice, suggesting that these hormones exert a stronger rapid glucose-raising effect in preadult life. Basal plasma glucose and insulin concentrations were lowest in young adult mice, and increased with advancing adult age. Glucose tolerance was best in young adult mice and deteriorated with age, while plasma insulin concentrations after administration of glucose, arginine and glucagon were lowest in young adult mice and increased with age. However, in response to these secretagogues, the percentage increase in plasma insulin above basal was reduced in older adult mice. This indicates a defect of stimulus-recognition-secretion-coupling in the B-cells of older adult mice. The raised plasma glucose concentrations of older adult mice could not be attributed to an increase in the acute hyperglycaemic action of glucagon or epinephrine. The hypoglycaemic response to exogenous insulin decreased with age, suggesting that tissue sensitivity to insulin was impaired. Treatment with growth hormone and cortisone for 5 days produced a greater antagonism of insulin in older mice than young adult or immature mice. Growth hormone impaired glucose tolerance at each age, but only produced a marked hyperinsulinaemia in older adult mice. In contrast, cortisone produced a marked hyperinsulinaemia at each age, but only impaired glucose tolerance in older adult mice.