Nicotine is the primary compound present in tobacco that is responsible for establishing and maintaining tobacco dependence; dependent smokers adjust their smoking behavior to maintain peripheral and central nicotine levels. CYP2A6 is the enzyme responsible for the majority of the inactivation of nicotine in humans. This enzyme is also responsible for activating tobacco-related procarcinogens such as the nitrosamines. This paper outlines how genetic variation in the CYP2A6 gene may protect individuals from becoming nicotine-dependent smokers, and if dependent, how impairment of the CYP2A6 gene function decreases the number of cigarettes consumed by smokers (Pianezza M, Sellers EM, Tyndale RF. 1998. A common genetic defect in nicotine metabolism decreases smoking. Nature 393(6687):750). We also discuss recent findings which suggest that mimicking this gene defect by inhibiting CYP2A6 decreases nicotine metabolism and smoking. Further research is needed in order to improve our understanding of how genetic variation in CYP2A6 alters the risk for nicotine dependence and lowers nicotine consumption. This includes a better understanding of how the genetic variants alter nicotine metabolism in vivo in males and females as well as the role of CYP2A6 genetic variation in risk for tobacco-related cancers. In addition we need to gain a better understanding of how manipulating this enzyme could be used therapeutically in prevention and treatment of smoking as well as in exposure reduction.