Early clinical observations and subsequent prospective studies indicated that vagus nerve stimulation (VNS) had the potential to improve mood in patients with epilepsy. Subsequent studies have evaluated the effect of VNS in treatment-resistant major depression. These initial studies indicate a significant short- and long-term benefit of VNS on mood. Although the precise mechanisms underlying the antidepressant effect of VNS remain obscure, there is emerging evidence that VNS is associated with alteration of cerebrospinal fluid concentrations of various neurotransmitters. Furthermore, VNS impacts on functional activity of brain areas within the limbic system. This presentation will review the evidence for VNS as an antidepressant treatment and will review the potential neurobiological correlates of this effect. This will be compared with data from other brain stimulation approaches to treatment of depression. The implications of VNS for our understanding of functional models of depression will be discussed.