BACKGROUND: Tobacco use is a worldwide epidemic expected to cause 10 million annual deaths by 2020 globally. Newer pharmacotherapy increases the specificity of tobacco dependence treatment by affecting receptors mediating nicotine effects. OBJECTIVE: To review current and emerging pharmacotherapy for the treatment of tobacco use. METHODS: Articles retrieved with searches conducted through PubMed, Pharmaprojects database, Datamonitor, the Internet, and the author's personal files. RESULTS/CONCLUSIONS: Traditional drug therapy for tobacco dependence has treated tobacco dependence by replacing nicotine or mediating nicotine withdrawal and craving through neurotransmitter modulation. Varenicline, an alpha4beta2 nAChR partial agonist, is an emerging drug therapy that modifies tobacco use behavior by acting directly on nicotine receptors in the reward centers of the central nervous system. Available data suggests that varenicline is the most effective pharmacotherapy currently available. Drug development in the area of tobacco dependence is desperately needed in order to further decrease the death and disability associated with tobacco use.