Although smoking is the primary risk factor for most lung cancers, genetic predisposition may play an important role. Familial aggregation studies suggest a greater genetic component in the risk for younger individuals developing lung cancer, for lifetime nonsmokers, and possibly for women. Low-penetrance, high-prevalence polymorphic genes may explain part of this genetic predisposition. Functional polymorphisms of xenobiotic metabolism may alter the total exposure of tobacco carcinogens in the host. Subtle alterations in the DNA repair, inflammatory, and cell cycle pathways may also alter lung cancer susceptibility. The role of individual polymorphisms has been evaluated for several genes including the CYP and glutathione s-transferase superfamilies, and the NAT genes; DNA repair genes such as XPD (nucleotide excision pathway), XRCC1 (base excision pathway), and MGMT; and tumor suppressor or cell cycle genes such as p53. Molecular epidemiological studies are now focused on building larger databases from existing smaller studies and developing strategies to simultaneously evaluate multiple polymorphisms and genes within the same pathway.