Although smoking has been established as the most important cause of lung cancer, approximately 10% of patients with this malignancy have no history of smoking. The pathogenesis of tobacco-related lung carcinogenesis is becoming well characterized, but the molecular mechanisms of neoplastic transformation in never-smokers have not yet been adequately elucidated. Nevertheless, numerous recent studies have revealed a distinct biological process of malignant transformation with unique epidemiological and clinicopathological characteristics in never-smokers. The molecular pathways involved in the differential pattern of lung oncogenesis according to smoking status, however, remain fairly obscure. Researchers have studied several molecular pathways implicated in lung carcinogenesis in smokers and never-smokers, examining these processes at the genomic, epigenetic and proteomic level. The differential protein expression according to smoking status in critical signal transduction pathways has attracted scientific interest because of the possibilities of therapeutic intervention. In this Review we describe the best-characterized signaling pathways implicated in the transduction of proliferative signals and discuss the activity of these pathways in smokers and never-smokers.