The risk of cigarette smoking plays a pivotal role in increasing the incidence rates of lung cancer. This paper sheds new light on modeling the impact of cigarette smoking on lung cancer evolution, especially genetic instability and the number of gene mutations in the genome of stem cells. To handle this issue, we have set up stochastic multi-stage models to fit the data set of the probabilities of current and former smokers from the Nurses’ Health Study cohort of females (NHS) and the Health Professionals Follow up Study cohort of men (HPFS). Throughout this paper, we consider both mutation rates and clonal expansion rates as parameters in each compartment. For current and former smokers, three-driver mutations are most likely to take place in the progression of lung cancer under smoking risk. For current smokers, our findings reveal that two to sixteen gene mutations are required to obtain a cancerous cell among men and women in US. Moreover, two to six (eleven) cancermutations are available in the pathway to lung cancer among former smokers who have quit smoking for more (less) than ten years for both male and female patients. This highlights that cigarette smoking stimulates the number of driver mutations during lung tumorigenesis in both sexes. It is very crucial to examine the role of cigarette smoking in determining whether genomic instability is an early stage or late stage in the process of lung carcinogenesis.