Lung cancer is a leading clinical condition for the high rates of mortality throughout the world. For a long time, it was considered that the risk of lung cancer is associated with smoking. With the advent of new technologies that allowed better diagnostic approaches, knowledge on the genetic basis of lung cancer in never smokers is expanding. In an epidemiological and biological stand point, lung cancer in never smokers is now recognized as a distinct disease entity. In this review, we provide a comprehensive view of the factors that contribute to lung cancer in never smokers. Epidemiological and non-genetic factors such as pollution, occupational exposure, socioeconomic status, infections and medical history determine the risk of lung cancer in never smokers. With regard to genetic factors, chromosomal aberrations, gene polymorphisms, mutations and epigenetic changes in a variety of genes involved in drug metabolism, inflammation, DNA repair and cell proliferation exert a significant effect on the risk of lung cancer in never smokers. Interestingly, it is now believed that the risk of lung cancer is higher in women and the role of female hormones in lung cancer is gaining momentum. The fact that lung cancer is a disease of the smokers is slowly waning and a rethink on the risk factors that cause this disease is very much important. Recent advances using epigenetic screening suggests that lung cancer in never smokers is a distinct disease entity. Epidemiological and clinical studies that screen for lung cancer should opt for a biological rather than a clinical selection. Diagnostic and treatment strategies should be carefully planned for lung cancer patients without a history of smoking because of the differences in the genetics, epigenetics, pathobiology and treatment outcomes in these set of patients.