The rationale for a treatment trial of mifepristone in PTSD is based on the wealth of knowledge available about persistent alterations of the HPA axis in PTSD and their interactions with the central and autonomic nervous system and the immune system. The most consistent HPA axis findings in PTSD, taken together, suggest there is increased sensitivity to the effects of glucocorticoids in the presence of increased central activation of the HPA axis. Among the most replicated neuroendocrine findings have been of elevated levels of corticotropin-releasing factor (CRF) in the cerebrospinal fluid (CSF), an exaggerated cortisol response to emotional stressors, and an exaggerated suppression of cortisol to the synthetic glucocorticoid dexamethasone (DEX). The earliest studies of the effects of dexamethasone (DEX) using the standard 1.0 mg dose, found that PTSD, unlike major depression, was not associated with higher rates of cortisol non-suppression and there was a trend for lower cortisol levels post-DEX in PTSD. A lower dose (0.5 mg) was employed to test the hypothesis of enhanced suppression of cortisol to DEX in Vietnam Veterans with PTSD, which was confirmed. Since then, with few exceptions, greater suppression of cortisol to low-dose DEX has been found in PTSD subjects, compared to unexposed and/or trauma-exposed controls without PTSD, in diverse samples, including samples of persons exposed to combat, natural disasters, domestic violence, the Holocaust, and childhood physical and sexual abuse. Furthermore, the extent of cortisol suppression is associated with PTSD symptom severity. The finding of a greater down-regulation of lymphocyte GR post-DEX suggests that the dexamethasone suppression test (DST) findings may be attributable to more responsive glucocorticoid receptors. More recent studies have demonstrated increased suppression of ACTH to DEX confirming increased glucocorticoid responsivity at the level of the pituitary. The studies of the effects of DEX on HPA axis activity suggest there is enhanced negative feedback inhibition of the HPA axis in PTSD. Such inhibition could help to explain why despite evidence of central HPA axis activation and an exaggerated response of cortisol to stressors and to ACTH stimulation in PTSD, 24-hour basal cortisol levels are not typically elevated and indeed are even sometimes low.