Biologically active plasma free cortisol increases markedly in pregnancy. In this investigation the free cortisol index (FFI) in the plasma of pregnant and nonpregnant women was measured by a charcoal adsorption technique. The circadian FFI patterns were virtually identical in the two groups, but in gravid women there was a substantial and sustained elevation of the FFI. Sequential studies during gestation and post partum revealed increasing responsiveness of the maternal adrenal glands to adrenocorticotropic hormone (ACTH) and decreasing suppressibility of the FFI by dexamethasone as pregnancy advanced. Persistence of normal circadian rhythmicity in spite of a continuously elevated FFI and resistance to dexamethasone suppression suggest control of cortisol secretion by normal regulatory mechanisms in pregnancy with resetting of the maternal feedback mechanisms to higher levels. This resetting and the lack of manifestations of cortisol excess in pregnancy might result from tissue refractoriness to cortisol. Elevated free cortisol would be needed to maintain homeostasis. The necessary increase in the production of cortisol could be facilitated by an enhanced responsiveness of the maternal adrenal glands to ACTH.