: Treatment-resistant depression is one of the major challenges in clinical psychiatry, considering that its current treatments are far from optimal. Although known for decades, in the last few years vagus nerve stimulation (VNS) has become increasingly popular as a novel method of treatment of pharmacoresistant depression. In spite of an emerging body of literature concerning the effectiveness and potential mechanisms of action of VNS, some crucial questions regarding those issues remain to be answered. We review the pre-clinical and clinical literature relating to VNS, with the impact of studies of efficacy and safety in treatment of pharmacoresistant depression and also in other clinical applications in the field of psychiatric disorders. We conclude that in light of emerging reports, VNS warrants more controlled studies for the treatment of other forms of depression, including depression in a younger population, and also of other psychiatric disorders. Because of its safety, VNS could potentially become a treatment of choice in fields in which treatment procedures traditionally require the least aggressive methods.