In this NIDA P50 application, we propose to establish a new Center for Excellence dedicated to the development of more effective smoking cessation treatments. Current smoking cessation treatments are ineffective for the majority of smokers, and new strategies are urgently needed. We propose to build upon the successful translational research center we have established over the last two decades to continue the process of discovering novel and more efficacious treatments. We have initiated the development of a unique adaptive treatment strategy, which alters treatment according to the characteristics of individual smokers (e.g., genotype) and the initial response to nicotine replacement therapy (NRT) prior to the target quit-smoking date. In this innovative approach to NRT, nicotine patch treatment is initiated two weeks before the quit date, which has been shown to double rates of continuous smoking abstinence over those obtained using conventional NRT that begins on the quit date. By monitoring ad lib smoking during the two-week prequit period, we can adapt treatments so that smokers who do not respond favorably, in terms of a reduced ad lib smoking, may be offered rescue treatments that increase their chances of success. This adaptive treatment strategy will be pursued in a tightly interwoven set of preclinical and clinical projects and cores. The preclinical studies (Project 4) will screen novel candidate treatments in a rodent model of nicotine self administration and identify critical mechanisms of action. Proof-of-concept human studies (Project 2) will evaluate the effects of novel candidate treatments on ad lib smoking and stress-induced craving and smoking behavior. The neuroimaging study (Project 3) will seek to elucidate the brain mechanisms underlying the efficacy of cessation treatments, in order to identify treatments that may prove successful in smokers for whom NRT alone is not effective. Large-scale clinical trials will be conducted (Project 1) to evaluate the efficacy of candidate treatment suggested on the basis of preclinical and clinical results from the other projects. All of the studies using human subjects will be facilitated by our already-established multi-site human subjects recruitment network (Recruitment/ Screening Core). An Education Core will convey the knowledge gained in the research projects to trainees, scientists, and the public at large. Our Center will continue to serve as a national resource for the development of innovative and more effective smoking cessation treatments, and will also be a unique educational resource for researchers, clinicians, and policymakers dedicated to the improvement of public health through the promotion of smoking cessation.