This review presents a synthesis of a large body of seemingly inconsistent literature on the role of the locus coeruleus-norepinephrine (LC-NE) system and the corticotropin-releasing hormone (CRH)-median eminence system in mediating the CNS effects of stress and the therapeutic effects of antidepressant drugs. The clinical implications of these findings for the etiology and treatment of stress-related psychiatric disorders such as depression will be discussed.