Objective: The presence of both sympathetic activation-mediated triggers and parasympathetic activation-mediated substrates are required to initiate and maintain some forms of atrial fibrillation (AF). AF predominantly precipitated by parasympathetic stimulation is known as vagally-mediated AF (VM-AF). The role of novel drugs and molecular targeted gene therapy that modulate the autonomic nervous system are therapeutic options in this unique population with VM-AF. Here, we review the role of the sympatho-vagal balance in the genesis of AF and consider drug therapy for VM-AF. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement, literature search was conducted using the keywords “vagal”, “vagal nerve”, “vagus”, “vagus nerve”, and “atrial fibrillation”. Retrieved citations were first screened independently by 2 reviewers for inclusion and exclusion criteria. Results: A total of 14 studies and 3 practice guidelines from 1986-2017 were included. Only two clinical investigations evaluated the effectiveness of disopyramide and sotalol in human subjects with VM-AF. The potential role of antiarrhythmic drugs has been studied in animal models. Conclusion: Growing evidence suggests that the autonomic nervous system is integral in the development of some AF VM-AF. Novel medications and genetic targets are undergoing investigation with promising results.