Response to smoking cessation treatment programs sharply decreases when applied to smokers with psychiatric comorbidities. Consequently, the development of smoking cessation treatments that address the needs of psychiatric patients is greatly needed. The primary purpose of this article is to detail the process of development of an empirically informed, theoretically driven treatment program designed to aid multiply diagnosed smokers in their attempts to become tobacco free. Issues related to treating tobacco dependence in the persistently mentally ill are described. Our initial experience providing manualized, cognitive-behavioral smoking cessation treatment with adjunctive nicotine replacement therapy is detailed, along with the iterative process of manual development. Our current treatment program is illustrated with examples of clinical interactions, as well as a description of our ongoing evaluation of the utility and success of the clinic.