Numerous studies confirm that the vagus nerve stimulation (VNS) is an efficient, indirect neuromodulatory therapy with electrically induced current for epilepsy that cannot be treated by epilepsy surgery and is therapy-refractory and for drug therapy-refractory depression. VNS is an established, evidence-based and in the long-term cost-effective therapy in an interdisciplinary overall concept.Long-term data on the safety and tolerance of the method are available despite the heterogeneity of the patient populations. Stimulation-related side effects like hoarseness, paresthesia, cough or dyspnea depend on the stimulation strength and often decrease with continuing therapy duration in the following years. Stimulation-related side effects of VNS can be well influenced by modifying the stimulation parameters. Overall, the invasive vagus nerve stimulation may be considered as a safe and well-tolerated therapy option.For invasive and transcutaneous vagus nerve stimulation, antiepileptic and antidepressant as well as positive cognitive effects could be proven. In contrast to drugs, VNS has no negative effect on cognition. In many cases, an improvement of the quality of life is possible.iVNS therapy has a low probability of complete seizure-freedom in cases of focal and genetically generalized epilepsy. It must be considered as palliative therapy, which means that it does not lead to healing and requires the continuation of specific medication. The functional principle is a general reduction of the neuronal excitability. This effect is achieved by a slow increase of the effectiveness sometimes over several years. Responders are those patients who experience a 50% reduction of the seizure incidence. Some studies even reveal seizure-freedom in 20% of the cases. Currently, it is not possible to differentiate between potential responders and non-responders before therapy/implantation.The current technical developments of the iVNS generators of the new generation like closed-loop system (cardiac-based seizure detection, CBSD) reduce also the risk for SUDEP (sudden unexpected death in epilepsy patients), a very rare, lethal complication of epilepsies, beside the seizure severity.iVNS may deteriorate an existing sleep apnea syndrome and therefore requires possible therapy interruption during nighttime (day-night programming or magnet use) beside the close cooperation with sleep physicians.The evaluation of the numerous iVNS trials of the past two decades showed multiple positive effects on other immunological, cardiological, and gastroenterological diseases so that additional therapy indications may be expected depending on future study results. Currently, the vagus nerve stimulation is in the focus of research in the disciplines of psychology, immunology, cardiology as well as pain and plasticity research with the desired potential of future medical application.Beside invasive vagus nerve stimulation with implantation of an IPG and an electrode, also devices for transdermal and thus non-invasive vagus nerve stimulation have been developed during the last years. According to the data that are currently available, they are less effective with regard to the reduction of the seizure severity and duration in cases of therapy-refractory epilepsy and slightly less effective regarding the improvement of depression symptoms. In this context, studies are missing that confirm high evidence of effectiveness. The same is true for the other indications that have been mentioned like tinnitus, cephalgia, gastrointestinal complaints etc. Another disadvantage of transcutaneous vagus nerve stimulation is that the stimulators have to be applied actively by the patients and are not permanently active, in contrast to implanted iVNS therapy systems. So they are only intermittently active; furthermore, the therapy adherence is uncertain.