Much is now known about the carcinogens in cigarette smoke, their conversion to forms that react with DNA, and the miscoding properties of the resulting DNA adducts that cause the many genetic changes known to exist in human lung cancer. The chronic exposure of pulmonary DNA to a multitude of metabolically activated carcinogens is consistent with our current understanding of cancer as a disease resulting from many changes in key genes regulating growth. This review illustrates how this solid foundation of knowledge can be used to find new ways to prevent lung cancer. Three prevention-related topics are discussed: human uptake of tobacco carcinogens as a way of assessing risk and investigating mechanisms; individual differences in the metabolic activation and detoxification of carcinogens, which may relate to cancer susceptibility; and chemoprevention of lung cancer in smokers and ex-smokers. These new approaches are necessary as adjuncts to education and cessation efforts, which despite some success have not eliminated tobacco smoking.