Tobacco dependence results in an estimated 430,000 premature deaths and $72 billion in related costs per year in the United States. This chapter takes a multidisciplinary approach to reviewing the problem of tobacco dependence. Findings from preclinical animal studies of the neurobiology of nicotine and its reinforcing effects have been integrated with human clinical and population studies examining sex and ethnic differences, cognitive effects, various environmental risk factors, complex genetic traits, and prevention and cessation methods for tobacco dependence. In many respects, examination of social, behavioral, and genetic risk factors in humans has developed independently from basic animal research. Fortunately, there has been a greater collaboration and exchange of findings between the human and animal fields of research, prompted mainly by significant progress at the molecular genetic level. For example, present and future research is addressing the following important issues: the study of nicotine pharmacokinetics and gene‐environment interactions in families as they relate to tobacco dependence; the examination of gene‐environment interactions in the development and maintenance of nicotine addiction in well‐controlled conditions using animal models; and the extent to which genetic variation influences response to treatment for tobacco dependence. These converging lines of research will lead to an improved understanding of the complexities of tobacco dependence and its treatment.