Both the unpredictability of side-effects and efficacy of glucocorticoid treatment can be problematic during clinical treatment. Here we discuss the evidence that exists for the hypothesis that individual glucocorticoid sensitivity underlies this problem. We suggest that glucocorticoid sensitivity is actually much more dynamic and common than previously thought. It is postulated that acquired tissue-specific glucocorticoid resistance could play a role in the origin and pathogenesis of depression, autoimmune disorders and AIDS. Moreover, recent genetic research has shown mutations in the glucocorticoid receptor (GR) gene and GR protein which are suggested to play a role in the pathogenesis of leukaemia, hereditary glucocorticoid resistance and Nelson's syndrome. These findings indicate that variations in the GR and in glucocorticoid resistance play a central role in a wide variety of diseases.