To elucidate the effect of cigarette smoke on developing lung cancer among individuals, numerous genetic and epigenetic factors related to cigarette smoke-induced lung cancers have been widely investigated and a various genes, loci and pathways have been identified as candidates to date. However, the importance of these molecular alterations in the initiation and progression of lung cancer still remains imprecise and different molecules altered in lung cancer are being used for stratification of patients for targeted therapy. There are a number of molecular pathways involved in the development of lung cancer, and environmental factors related to these alterations are still unclear. Furthermore, various genetic alterations determined by candidate gene approach have not been re-evaluated for their functional significance together with epigenetic alterations in the same population. Accumulated evidence suggested that lung cancer in ever smokers and never smokers follow distinct molecular pathways and may therefore respond to distinct therapy. Therefore, additional studies will be essential to re-evaluate the individual risk of developing lung cancer based on the combination of genetic and epigenetic alterations and to set up a guideline to assess the individual risk for lung cancer and for its prevention.