The devastating consequences of tobacco smoking for individuals and societies motivate studies to identify and understand the biological pathways that drive smoking behaviors, so that more effective preventions and treatments can be developed. Cigarette smokers respond to nicotine in different ways, with a small number of smokers remaining lifelong low-level smokers who never exhibit any symptoms of dependence, and a larger group becoming nicotine dependent. Whether or not a smoker transitions to nicotine dependence has clear genetic contributions, and variants in the genes encoding the α5-α3-β4 nicotinic receptor subunits most strongly contribute to differences in the risk for developing nicotine dependence among smokers. More recent work reveals a differential response to pharmacologic treatment for smoking cessation based on these same genetic variants in the α5-α3-β4 nicotinic receptor gene cluster. We anticipate a continuing acceleration of the translation of genetic discoveries into more successful treatment for smoking cessation. Given that over 400,000 people in the United States and over 5 million people world-wide die each year from smoking related illnesses, an improved understanding of the mechanisms underlying smoking behavior and smoking cessation must be a high public health priority so we can best intervene at both the public health level and the individual level.