With more than 16,000 patients implanted with the vagus nerve stimulation (VNS) therapy system (Cyberonics, Inc., Houston, Texas), VNS therapy has assumed an increasingly important role in the treatment of medically refractory seizures since its approval 5 years ago by the United States FDA. This review discusses the clinical trials that provided evidence for the approval, long-term efficacy, efficacy in special populations and co-morbid conditions, and safety and tolerability. Additional studies are suggested to further explore the capabilities of VNS therapy.