Cigarette smoking is the most established risk factor for lung carcinogenesis; however, its effects on the progression of lung cancer are still unclear. We reviewed the clinical investigations on this issue, which imply that smoking status is a treatment predictor and prognostic factor for several subtypes of lung cancer. Moreover, gene alterations and various protein expressions of tumor progression were recognized more frequently in the tumor tissues of smokers than in those of the never smokers. A cellular analysis revealed that tobacco-specific chemical compounds cause genetic or epigenetic alterations, modulate expressions of large numbers of genes that include molecules related to proliferation, invasion and metastasis, and deteriorate anti-tumor immunity. Our findings suggest that smoking promotes the progression of lung cancer, and that elucidating the molecular mechanisms may help to clarify the therapeutic targets.