Neonatal rats exhibit a period of diminished pituitary and adrenocortical responses to stress during the first 2 weeks of life. Since thyroid hormones are known to affect brain development, modulation of these responses to stress by alterations in thyroid hormone status have been investigated in hypothyroid (Hypo) and hyperthyroid (Hyper) rat pups. Changes in ACTH and corticosterone (B) levels were measured under basal and stress conditions (3 min exposure to ether vapors) in neonates of various ages (day 5–21). Basal T<sub>4</sub> and corticosterone-binding globulin (CBG) levels were also measured. Hypo pups were obtained from methimazole-treated mothers and hyperthyroidism was induced by daily subcutaneous injections of L-T<sub>4</sub> (100 µg/kg BW) from birth on. In Hyper rats, premature onset of ACTH and B responses to stress was observed in 5-day-old rats while significant ACTH and B secretion only appeared by day 10 in vehicle-injected rats. By contrast, ACTH and B responses to stress were delayed in Hypo pups and only occurred by day 21. The lack of ACTH and B responses to stress of 14-day-old Hypo rats could be reversed by one single L-T<sub>4</sub> injection (100 µg/kg BW) given 24 h, but not 4 h prior to exposure to stress. On day 21, smaller (p < 0.05) stress-induced ACTH release was observed both in Hypo and Hyper rats compared to intact rats, concomitant with a diminished ACTH secretion following exogenous ovine CRF(10 µg/kg BW, i.p.) administration. T<sub>4</sub> treatment increased pituitary ACTH stores and produced marked increases in plasma B (4.5-fold on day 5, 2.5-fold on day 21), and CBG concentrations (2-fold on day 5, 2.6-fold on day 21) at all ages. In contrast, Hypo rats exhibited no changes in pituitary ACTH stores, but reduced plasma CBG concentrations throughout the neonatal period. Basal plasma B levels were increased in Hypo rats on day 5 and 10 comparable on day 14 or diminshed on day 21 as compared to intact rats, suggesting that the normal developmental pattern of B is delayed in hypothyroidism. In conclusion, we have shown that (1) thyroid hormones modulate the onset of ACTH and B responses to stress, most likely via changes in B and CBG concentrations, (2) the lack of ACTH and B response to stress in hypothyroid rats can be restored by one single injection of L-T<sub>4</sub> and (3) a diminished ACTH and B response to stress observed at weaning in Hypo and Hyper rats is associated with a decrease in pituitary sensitivity to exogenous CRF.