The dexamethasone suppression test (DST) has had unprecedented evaluation among biological tests proposed for clinical use in psychiatry. It is hypothesized to reflect pathophysiologic changes at the CNS level. The sensitivity of the DST (rate of a positive outcome, or nonsuppression of cortisol) in major depression is modest (about 40%- 50%) but is higher (about 60%-70%) in very severe, especially psychotic, affective disorders, including major depression with psychotic as well as melancholic features, mania, and schizoaffective disorder. The specificity (true negative outcome) of the DST in normal control subjects is above 90%, but it varies from less than 70% to more than 90% in psychiatric conditions that often need to be separated from major affective disorders. In dementia the specificity is even lower. In addition, a number of medical conditions, including severe weight loss and use of alcohol and certain other drugs (barbiturates, anticonvulsants, and others), can produce false positive results. Positive initial DST status in major depression does not add significantly to the likelihood of antidepressant response, and a negative test is not an indication for withholding antidepressant treatment. Some recent data suggest that DST-positive depressions (cortisol nonsuppression) are less likely than DST-negative cases (cortisol suppression) to respond to a placebo. If this is confirmed, it would increase the real magnitude of the difference in treatment response between DST-positive and DST-negative depressed patients. Failure to convert to normal suppression of cortisol with apparent recovery from depression suggests an increased risk for relapse into depression or suicidal behavior. Although the clinical utility of the DST as currently understood is limited, in certain specific situations its thoughtful use may aid clinical decision making. The association of an abnormal test result with major affective disorders encourages continued research on the DST.Abstract Teaser