Environmental stimuli and drugs affect the norepinephrine (NE) system and may be linked to the manifestation and treatment of anxiety and affective disorders. The activity of locus ceruleus NE neurons in the brainstem can alter the function of forebrain structures associated with several psychiatric disorders. In particular, NE neurons send and receive projections from sensory afferents, limbic areas, and cortical areas implicated in higher-order brain malfunctions and the symptomatology of anxiety and affective disorders. In turn, anxiolytic and antidepressant drugs are able to offset perturbations of NE activity and forebrain structures with a time course congruent with their therapeutic action. All antidepressants, even the agents selective for other biogenic amines or peptides, act on the NE system. In the present review, the effects of antidepressants on NE neurons are summarized and applied to the treatment of neuropsychiatric disorders, with emphasis placed on mechanisms of action.