Lung cancer is the leading cause of cancer related deaths in the United States. Radiation therapy, either alone or in combination with systemic chemotherapy, is one of the main treatment modalities for locally advanced non-small cell lung cancer (NSCLC). Recently, driven by a better understanding of the molecular oncogenic drivers involved in lung tumorigenesis, targeted systemic therapies have been developed clinically to generate higher response rates and longer overall survival in a genetically stratified population of lung cancer patients. For example, erlotinib and gefitinib have produced up to 85 percent response rates and longer overall survival in patients with NSCLC who harbor selective EGFR kinase domain (KD) mutations when compared to conventional chemotherapies. However, our understanding of how specific oncogenic drivers in NSCLC impact their sensitivity to radiation therapy or combination chemo-radiation therapy is limited and has not been systematically studied in vivo pre- clinically. In this proposal, as outlined in the specific aims below, we propose to employ our well characterized genetically engineered mouse models of lung cancer based on inducible lung epithelium specific expression of the common lung cancer relevant oncogenic drivers (EGFR kinase domain mutants, EGFRvIII mutant and KRAS mutants) along with the latest small animal focal irradiator platform to dissect the differential sensitivity of the defined oncogene driven lung cancer to radiation therapy and combined chemo-radiation therapy in vivo. Data from the successful completion of the aims will help facilitate the identification of genotype specific lung cancers that are radiosensitive, help rationally integrate radiation therapy with targeted therapeutics and, thus, advance the care and treatment of lung cancer patients.