Vagus nerve stimulation (VNS) is an established treatment of medically refractory partial-onset seizures. Recent data from an open-label multicenter pilot study also suggest a potential clinical usefulness in the acute and maintenance treatment of drug-resistant depressive disorder. Despite the fact that surgery is needed to implant the stimulating device, the option of long-term use largely devoid of severe side effects would give this treatment modality a privileged place in the management of drug-resistant depression. However, definite therapeutic effects of clinical significance remain to be confirmed in large, placebo-controlled trials. Besides the potential clinical usefulness, VNS can be used as a research tool in epilepsy patients implanted for clinical reasons, allowing neurophysiologic investigations of the parasympathetic system and its interactions with other parts of the central nervous system.