Despite a number of overlapping symptoms, individuals with posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) often display hypothalamic-pituitary-adrenal (HPA) profiles that appear quite different from one another. This review describes the patterns of HPA-axis activity and reactivity in healthy individuals compared to individuals with these two disorders. Measures of HPA-axis activity and reactivity include cortisol levels at rest, in response to the dexamethasone suppression test (DST), and in response to psychological stress. The research reviewed presents the possibility of diagnostic specificity with regard to HPA function. In particular, the differential response pattern to the DST suggests that, while it cannot be considered a pure diagnostic tool, it should be one measure taken into consideration during diagnosis.