It is well-known that tobacco smoke is a definite causative agent important for human health. Epidemiological research has proven that smoking is a cause of various serious and fatal diseases. However, never-smokers comprise a high proportion of non-small-cell lung cancer (NSCLC) patients. To determine whether lung cancer patients in never smokers have different genetic mutations from their counterparts in smokers, we comprehensively searched the Cochrane Library, Medline and EMbase from 1966 to Jun 2010 for the following terms: (“non-smoker” or “never-smoker”) and (“lung cancer”) and (“gene”) limited to English and clinical trials. Although a significant fraction of lung cancers in never smokers may also be attributable to tobacco, many such cancers arise in the absence of detectable tobacco exposure, and may follow a very different molecular pathway of malignant formation, including EGFR gene mutation, P53 mutation and metabolic gene CYP1AIIle462Val polymorphism. These genes will help doctors to separate never-smoker lung cancer from smokers, and may present promising targets for therapy of never-smoker lung cancers. Future efforts should focus on further delineation of underlying biologic differences, identifying potential non-tobacco-related risk factors, and refining treatment strategies for different groups of lung cancerpatients.