Nicotine dependence has a complex multifactorial etiology, underscoring the value of applying a transdisciplinary research model. The important goal of treating nicotine dependence can be realized by transdisciplinary research that translates discoveries in basic neuroscience, pharmacology, genetics, and behavioral science to develop new treatment models that can be translated readily into the clinic and community. As part of this special issue highlighting work at the Transdisciplinary Tobacco Use Research Centers (TTURCs), we describe transdisciplinary research at the University of Pennsylvania TTURC aimed at elucidating the neurobiological and genetic basis of nicotine dependence, the development of novel medications, and the translation of this research to practice.