Following exposure to stress, cortisol is secreted from the adrenal cortex under the control of the hypothalamic-pituitary-adrenal axis (HPA-axis). Central in the regulation of the HPA-axis is a two tied corticosteroid-receptor system, comprised of high and low affinity receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), respectively. In addition, these corticosteroid receptors mediate the effects of cortisol during stress on both central and peripheral targets. Cortisol modulates gene-expression of corticosteroid-responsive genes, with the effect lasting from hours to days. Mutations in the GR-gene are being associated with corticosteroid resistance and haematological malignancies, although these mutations are relatively rare and probably not a common cause of these diseases. However, several GR-gene variants and single nucleotide polymorphisms (SNP) in the GR-gene have been identified which are relatively common in the human population. The GRbeta-variant, for example, has been proposed to influence corticosteroid-sensitivity and most evidence has been derived from the immune system and in particular asthma. With respect to polymorphisms, a BclI restriction fragment polymorphism and a Asp363Ser have been described, which not only influence the regulation of the HPA-axis, but are also associated with changes in metabolism and cardiovascular control. These associations of a GR-gene polymorphism with metabolism and cardivascular control, and also with the regulation of the HPA-axis, indicates an important underlying role of cortisol in the etiology of these complex disorders. Therefore, we propose that a common underlying defect in these complex disorders is a disregulation of the HPA-axis, especially during stress. The clinical implication is that the regulation of the HPA-axis should be envisioned as a primary target of new drugs for the treatment of stress-related disorders.