Abstract Lung cancer is the leading cause of cancer-related deaths in both men and women with a 5-year survival rate of only 19%. Although PD-1 immune checkpoint blockade therapy may improve these outcomes, the majority of lung cancer patients still fail this innovative immunotherapy. One major obstacle in the lung cancer field is the lack of faithful models that are suitable to identify mechanisms underlying the initiation and progression and metastasis of human lung cancer and to test new therapeutic strategies against this number 1 cancer killer. Xenograft, syngeneic or humanized mouse models using established cancer cell lines cannot recapitulate the natural coevolution of cancer and stromal cells as well as their intricate interplay in the complex micro- environment. Furthermore, using immunocompromised mice for xenograft transplants precludes the critical interaction between cancer cells and the immune system. To meet this important challenge, we have recently generated a novel mouse model of lung cancer, with the full process from tumor initiation to regional and distant metastasis at a penetrance of 100%. Notably, the metastasis pattern in this endogenous lung cancer model closely resembles that of its human counterpart in patients. In this application we will systematically characterize this model, and importantly, examine if it replicates human lung cancer molecularly, genetically and immuno-phenotypically. We will also establish several complementary models and incorporate them with the imaging markers luciferase and enhanced green fluorescent protein (EGFP) allowing monitoring and tracking tumor development and metastasis non-invasively in vivo. These studies will establish faithful models and provide fundamental knowledge on human lung cancer. They are also highly significant to the cancer field at large, given the currently limited knowledge on cancer, and in particular, the full process from tumor initiation to regional and distant metastasis in general.