The Multiethnic Cohort Study has demonstrated that African Americans and Native Hawaiians have a higher risk for lung cancer due to cigarette smoking than Whites while Latinos and Japanese Americans have a lower risk. These findings are consistent with other epidemiologic studies in the literature. In this review, we summarize tobacco carcinogen and toxicant biomarker studies and genetic analyses which partially explain these differences. As determined by measurement of total nicotine equivalents in urine, which account for about 85% of the nicotine dose, African Americans take up greater amounts of nicotine than Whites per cigarette while Japanese Americans take up less. There are corresponding differences in the uptake of tobacco smoke carcinogens such as tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, 1,3-butadiene, and other toxic volatiles. The lower nicotine uptake of Japanese Americans is clearly linked to the preponderance of low activity forms of the primary nicotine metabolizing enzyme CYP2A6 in this ethnic group, leading to more unchanged nicotine in the body and thus lower smoking intensity. But the relatively high risk of Native Hawaiians and the low risk of Latino smokers for lung cancer are not explained by these factors. The possible role of epigenetics in modifying lung cancer risk among smokers is also discussed here. The results of these published studies may lead to a better understanding of susceptibility factors for lung cancer in cigarette smokers thus potentially identifying biomarkers that can detect those individuals at highest risk so that preventive approaches can be initiated at an early stage of the lung cancer development process.