Tobacco addiction is the most significant preventable cause of morbidity and mortality in the Western world, with >430,000 deaths annually from tobacco-related diseases being reported in the United States. Although effective treatments are available for cessation of smoking (e.g., nicotine replacement therapies, sustained-release bupropion and varenicline), they do not work for all smokers. Therefore the development of more effective medications for treating tobacco dependence, based on novel mechanisms, is a high priority. This article reviews the links between smoking and monoamine oxidase (MAO) inhibition, which could lead to the development of novel pharmacotherapies to treat tobacco dependence.