Increased levels of glucocorticoid hormones-the main product of the hypothalamic-pituitary-adrenal (HPA) axis-have been considered to be "depressogenic," but this notion has largely derived from studies in patients with endocrine conditions, such as Cushing's syndrome or exogenous treatment with synthetic glucocorticoids. In these conditions, it is likely that the full impact of the high glucocorticoid levels is felt on the brain, through over-stimulation of the glucocorticoid receptors (GRs); indeed, normalizing these high levels leads to an improvement of mood in these patients. However, a completely different mechanism may be operating in major depression, where the increased levels of glucocorticoid hormones are conceptualized as driven by an impairment in GR function (glucocorticoid resistance), and therefore as a "compensatory" mechanism. Moreover, clinical and experimental studies have shown that antidepressants increase GR function, thus leading to resolution of glucocorticoid resistance. Interestingly, a number of studies have also demonstrated that manipulating GR function with both agonists and antagonists has an antidepressant effect, and indeed that other drugs targeting the HPA axis and cortisol secretion-even drugs with opposite effects on the HPA axis-have antidepressant effects. These studies do not support the notion that "high levels of glucocorticoids" always have a depressogenic effect, nor that decreasing the effects of these hormones always has an antidepressant effects.