Although rates of tobacco use and dependence have been reduced substantially since the 1960s, one in five Americans continues to smoke. The prevalence of smoking appears to be substantially higher in persons with psychiatric and substance use disorders, and these individuals also have less success when they attempt smoking cessation. In this chapter we review the epidemiology of tobacco use and dependence and the pharmacological effects of nicotine and tobacco and discuss the clinical assessment of tobacco users. We then review behavioral and pharmacological treatments, including the U.S. Food and Drug Administration (FDA)–approved pharmacotherapies: nicotine replacement therapies (NRTs), sustained-release bupropion, and varenicline. Finally, we discuss the integration of tobacco dependence treatment into mental health settings with the view that tobacco dependence is a chronic medical disorder and that more effective treatment of this comorbidity in psychiatric disorders may require targeted treatments based on a better understanding of the pathophysiology of individual psychiatric disorders.