A confluence of evidence indicates that alterations in hypothalamic-pituitary-adrenal regulation can have profound effects on the symptom picture of psychiatric illnesses and that therapeutic interventions directly targeted at corticosteroid metabolism may have clinical benefit. This paper reviews the varying lines of inference that support such a hypothesis and reviews work by our group and others utilizing the cortisol synthesis inhibitor, ketoconazole and, more recently, dehydroepiandrosterone (DHEA), as potential novel mood-altering agents. The data thus far suggest that antiglucocorticoid drug treatment may be useful in certain subgroups of depressed patients and may offer a theoretical rationale for alternative drug design.