Cigarette smoking is the major cause of lung cancer, the largest cancer killer in the world. This chapter discusses the role of cigarette smoke carcinogens as causes of lung cancer. A general mechanistic framework is presented, in which cigarette smoke carcinogens and their metabolically activated forms cause mutations in critical growth control genes, along with other effects. Evidence and unresolved issues for the role of various groups of carcinogens, such as polycyclic aromatic hydrocarbons, nitrosamines, volatile organic compounds, and metals as causes of lung cancer are discussed. An overview of inhalation studies of cigarette smoke in laboratory animals is also presented. Collectively, the massive studies on carcinogenesis by cigarette smoke and its constituents provide a firm base for understanding the mechanisms of human lung carcinogenesis.