Posttraumatic stress disorder (PTSD) is typically accompanied by acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but several studies have also used a challenge model to further assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. This paper reviews common methodology and research findings on HPA function in PTSD, and discusses the pathophysiological mechanisms underlying these findings. We reviewed the literature and selected all English-language, human subject, data driven, pharmacological and non-pharmacological challenge studies pertaining to the HPA axis, and in vitro leukocyte glucocorticoid receptor studies in adult PTSD subjects. Studies using a non-pharmacological stress paradigm (cognitive stress, trauma reminders) to stimulate the HPA axis showed an exaggerated cortisol response in PTSD. The most widely used pharmacological challenge with consistent results was the low dose dexamethasone-suppression test (DST). These DST studies showed enhanced cortisol suppression in subjects with PTSD. Different hypotheses have been purported to explain the alterations in HPA axis functioning in PTSD. The results of the reviewed challenge tests, however, did not exclusively support one of the hypothesized mechanisms. Further research assessing hormones at all levels of the HPA axis at both baseline and at challenge conditions with a proper stratification of study population, will be necessary for a better understanding of stress-responsivity on the level of the HPA axis in PTSD.