Globally, tobacco smoking is responsible for the deaths of five million people each year and increases the risk of developing numerous disorders, particularly pulmonary and cardiovascular disease, as well as many cancers. It has long been known that several environmental factors influence the decision to smoke. However, in recent years, we have learned more about the role that genes play in the development of nicotine dependence. Twin and family studies have shown that there is not one specific gene that determines who will develop a smoking addiction but rather several genes that cause an individual to become more susceptible to being addicted to nicotine. These genes are responsible for how certain neurotransmitters are produced and metabolized, the number of receptors that are available to act on and how rapidly nicotine is metabolized by the individual. The more we understand these processes, the better the opportunity will be to formulate effective treatments. This review discusses the role genetics plays in the decision to smoke, the ability to quit and how human genetic variation can influence the success of therapeutics in the treatment of smoking behavior.