Accumulating data support the role of genetic factors in smoking initiation, progression to tobacco dependence, and smoking persistence. This review summarizes current research on the heritability of tobacco use phenotypes and genetic association studies of smoking-related behaviors. Although progress has been made in genetics research on smoking behavior, many studies have methodological limitations, including insufficient samples for detecting gene-gene and gene-environment interactions and use of less refined phenotypes. Pharmacogenetic investigations also are identifying variants in drug-metabolizing enzymes, receptors, and transporters that modify therapeutic response to smoking cessation medications; however, the field is relatively new, and most findings in this area have yet to be replicated. As this research advances, it will be important to study and address practical, economic, ethical, and social barriers to the translation of genetics research on tobacco use to clinical practice.