Tobacco use exerts a huge toll on persons with mental illnesses and substance abuse disorders, accounting for 200,000 of the annual 443,000 annual tobacco-related deaths in the United States. Persons with chronic mental illness die 25 years earlier than the general population does, and smoking is the major contributor to that premature mortality. This population consumes 44% of all cigarettes, reflecting very high prevalence rates plus heavy smoking by users. The pattern reflects a combination of biological, psychosocial, cultural, and tobacco industry-related factors. Although provider and patient perspectives are changing, smoking has been a historically accepted part of behavioral health settings. Additional harm results from the economic burden imposed by purchasing cigarettes and enduring the stigma attached to smoking. Tailored treatment for this population involves standard cessation treatments including counseling, medications, and telephone quitlines. Further progress depends on clinician and patient education, expanded access to treatment, and the resolution of existing knowledge gaps.