One of the pitfalls of biomarker research is that it is often difficult to distinguish between a potential biological marker present in association with a disorder (in this case post-traumatic stress disorder (PTSD)) and a biological alteration that is indicative of the pathophysiological process that results in disorder. The former may be useful in predicting or diagnosing PTSD, but may not necessarily be a viable treatment target. This presentation will discuss the evidence for glucocorticoid dysregulation in PTSD that has nominated the hypothalamic-pituitary-adrenal (HPA) axis as a potential target of intervention. To date, most studies of glucocorticoid dysregulation have focused on cross-sectional evaluation of persons with chronic PTSD, or have used prospective, longitudinal approaches following trauma-exposed persons in the immediate aftermath of trauma exposure or even, prior to their exposure to critical incidents. Persuasive data have also been obtained by evaluating the effects of a single dose of glucocorticoids on relevant PTSD behaviors and biology. Other approaches involve understanding how glucocorticoid-related alterations change in response to treatment. In studies of civilians and combat veterans, glucocorticoid-based markers such as urinary cortisol and cortisol-related metabolites predicted treatment outcomes, and some markers also associated with symptom improvement. In combat veterans, glucocorticoid receptor sensitivity, glucocorticoid genotype, and epigenetic alterations on the glucocorticoid receptor were predictors of treatment response and correlates of recovery. These findings have provided support for initial trials of hydrocortisone in PTSD prophylaxis during the golden hours, in the acute aftermath of trauma.