Stress is an ubiquitous phenomenon with significant impact on human physiology when it lasts too long, when it is too intense, or when it hits vulnerable individuals. Examining the mechanisms linking stress exposure with health and disease is an important endeavor in psychoneuroendocrine research. Empirical evidence so far revealed large intra- as well as inter-individual variability in hypothalamic-pituitary-adrenal (HPA) axis responses to acute psychosocial stress, showing that the HPA axis is a highly adaptive system. Thus, the characterization of intra- und inter-individual patterns of HPA axis reactivity is of high scientific interest and forms the basis on which mechanistic links between stress response (dys)regulation and health impairments can be examined. To date, basic knowledge has been, and still is, accumulated on demographic, biological (including genetic and epigenetic) factors, lifestyle behavioral variables, consumption of substances and medication, psychological and personality factors, as well as on methodological aspects. Besides this, there is also very recent progress in respect to the development of laboratory stress paradigms that can be applied in virtual reality or inside an MRI-scanner. In sum, the present review updates our current knowledge on moderating and intervening factors as sources of intra- und inter-individual variability in human cortisol stress responses and offers recommendations for future research designs.