Therapeutic brain stimulation through left cervical VNS now has established safety and efficacy as a long-term adjunct treatment for medication-resistant epilepsy. There is considerable evidence from both animal and human studies that the vagus nerve carries afferent signals to limbic and higher cortical brain regions, providing a rationale for its possible role in the treatment of psychiatric disorders. Open-label studies in patients with treatment-resistant depression have produced promising results, especially when response rates at longer term (1 year and 2 years) follow-up time points are considered. Short-term (10 weeks) treatment with VNS failed to demonstrate statistical superiority over sham treatment in a recently completed double-blind study, so antidepressant efficacy has not yet been established. Longer term data on VNS in depressed patients as well as further information regarding the possible dose-response relation will help to determine the place of VNS in the armament of therapeutic modalities available for major depression.