Vagus nerve stimulation (VNS) is an established anticonvulsant therapy in treatment-resistant patients with epilepsy. The known anatomical projections of the vagus nerve to many brain regions that have been implicated in mood disorders suggest that VNS may also have useful antidepressant effects. There has been growing interest in the potential application of VNS in the nonpharmacological management of treatment-resistant depression. Results from an open-label study, in which 59 subjects with treatment-resistant depression were treated for 10 weeks with VNS therapy, reported a 31% response rate. In a recent controlled double-blind trial of VNS and depression, short-term treatment for 10 weeks failed to demonstrate statistical improvement over sham treatment. Results from the long-term phase of this trial may be more significant, however published data are awaited.