The vagus nerve is a major component of the autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the neuro-endocrine-immune axis. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve. Left cervical VNS is an approved therapy for refractory epilepsy and treatment-resistant depression. Right cervical VNS has proven effective for treating heart failure in preclinical studies and a Phase II clinical trial. The effectiveness of noninvasive transcutaneous VNS for epilepsy, depression, and other conditions has not been investigated beyond small pilot studies. The relationship between depression, inflammation, and cardiovascular, cerebrovascular, and metabolic syndromes might be mediated by the vagus nerve. Transcutaneous VNS deserves further study as an antidepressant therapy and for its potential effect on physiological biomarkers associated with depression morbidity and mortality.