NSCLC is a heterogeneous disorder consisting of distinct molecular subtypes which can be treated by using specific drugs targeted to distinct genetic lesions. It is well known that NSCLS incidence is higher in chronic obstructive pulmonary disease (COPD) patients because they share a common risk factor (cigarette smoking) and it is believed that the typical inflammatory microenvironment observed in COPD may influence the molecular mechanisms responsible of carcinogenesis. In the last years, the role of epigenetic processes in cell biology and tissue pathology has been extensively studied both in COPD and NSCLC. The recent paper by Wauters et al. showed a specific pattern of driver mutations and molecular features in NSCLC raising in the context of COPD. All these findings have shown for the first time that lung tumors found in COPD patients differ from those observed in patient without COPD due to the presence of a specific tumor microenvironment which is characterized by reduced CD4+ Treg cells. On this basis, the present work aims at discussing and analyzing the context-specific mechanisms of clonal selection and evolution mainly focusing on the epigenetic alterations and at pointing out the potential therapeutic implications.