The hypothalamus-pituitary-adrenal-axis (hpa-axis) dysregulation is the most widely researched biological defect in depression. In recent years great progress has been made in the inventory of many aspects of the hpa-axis in general and in depression in particular. The new insights are concerned with the relation between the hpa-axis and the limbic system, the damaging effects of cortisol on cognitive functions and the protective role which the hormone dehydroepiandrosterone (dhea) possibly plays on this. Owing to these insights, the relevance of the hpa-axis in clinical practice has strongly increased.