To advance the science of tobacco control, an enhanced understanding of the bio-behavioral basis of nicotine addiction is needed. In this study, we provide an overview of data from investigations of genetic factors in smoking behavior, discuss potential bio-behavioral mechanisms and effect modifiers, and suggest avenues for pharmacogenetics research in the area of smoking cessation treatment. The evidence to date is very consistent with respect to the significance of genetic contributions to smoking behavior. However, attempts to elucidate the role of specific genetic variants have met with mixed success. Explanations for the lack of consistency in the results of genetic association studies include biases in ascertainment, ethnic admixture, lack of attention to co-variates or modifiers of genetic risk, and the need for more refined phenotypes. As the field of genetics and smoking research progresses, increasing attention is being devoted to gene-environment interactions, with particular attention to the identification of genetic variants that may modify the effects of pharmacological treatment for smoking. With advances in molecular biology and genomics technology, individualized tailoring of smoking cessation therapy to genotype is within our grasp. Such research has the potential to improve treatment outcome, thereby reducing morbidity and mortality from smoking-related disease.