This study investigated the effects of acute and chronic restraint stress during the third week of pregnancy on placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity in rats. Acute exposure to stress on gestational day 20 immediately up-regulated placental 11β-HSD2 activity by 160%, while chronic stress from day 14 to day 19 of pregnancy did not significantly alter basal 11β-HSD2 activity. However, the latter reduced the capacity to up-regulate placental 11β-HSD2 activity in the face of an acute stressor by 90%. Thus, immediate up-regulation of 11β-HSD2, the feto-placental barrier to maternal corticosteroids, may protect the fetus against stress-induced high levels of maternal corticosteroids, but exposure to chronic stress greatly diminishes this protection.