Lung cancer is the leading cause of cancer mortality worldwide. There have been only slight improvements in early diagnosis and survival, reflecting limited advances in screening and treatment for lung cancer. The identification of host differences in susceptibility to lung carcinogens, in particular to cigarette smoke, is essential in predicting who is at highest risk. Susceptibility differences in the form of rare, high-penetrance genes are suggested from studies of familial aggregation of lung cancer and a linkage study. Studies focused on more common, low-penetrance genes in the tobacco smoke metabolism pathways (phase I and phase II enzymes) and DNA repair pathways are reviewed, as are inflammation and cell cycle-related genes and DNA adducts as intermediate biomarkers. Also reviewed are studies of epigenetic mechanisms, such as methylation, as alternative sources of variation in host susceptibility. Studies of molecular epidemiology in lung cancer survival are discussed briefly. In the future, studies that focus on complex interactions between multiple genes and environmental exposures within pertinent pathways are needed. New technological advances in genotyping will help move the field forward.