The hypothalamus pituitary adrenal (HPA)- axis is one of the major output systems of the neuroendocrine stress response. Its major end products, glucocorticoids (GCs), have a plethora of effects throughout the organism, most of which are believed to be protective against disturbances of homeostasis. However, negative effects have also been described under specific conditions of hyper- or hypo(re)activity of the HPA axis. Both beneficial and adverse effects of GCs ultimately depend on the target tissue sensitivity to these steroids. Recent findings suggest that GC sensitivity (a) may vary between different target tissues in the same organism, (b) shows large individual differences and (c) can be acutely changed in times of acute stress. In the present review, data are summarized which show differences in GC sensitivities in patients suffering from diverse somatic and psychiatric diseases, as well as chronically stressed individuals. Furthermore, studies are presented that show a rapid modulation of GC sensitivity in response to exercise or psychosocial stress in healthy adults. The response pattern of acute GC sensitivity modulation seems to be influenced by age and sex hormone status of the individual. While the GC signalling cascade may be subject to modulation at several levels, the pathway for acute modulation of GC sensitivity remains to be elucidated.