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Vagus nerve stimulation (VNS) has become an established therapy for difficult-to-treat epilepsy during the past 20 years. The vagus nerve provides a unique entrance to the brain. Electrical stimulation of this structure in the cervical region allows direct modulative access to subcortical brain areas, requiring only minimally invasive surgery with low risks involved. VNS therapy has shown to reduce epileptic seizures both in number and severity in a group of patients not responding to antiepileptic drugs. The effects are accompanied by an atypical set of central side effects. After the success of the VNS therapy with epilepsy, the technique has been applied to a wide variety of disorders, ranging from major depressive disorder to Alzheimer's disease. The results of several of these are promising. In this review, the results as well as the rationale for the different applications of VNS are discussed.