Lung adenocarcinoma is the leading cause of cancer deaths in the United States each year, and there is an unmet need for therapies effective in advanced disease. Recent developments in next generation sequencing have enabled the characterization of the mutational spectrum of lung adenocarcinoma, revealing an abundance of inactivating mutations that have not been thoroughly studied. Therefore, it remains to be seen whether these genes have tumor suppressive functions in lung adenocarcinoma, and whether they may provide new therapeutic avenues. To address these questions, we utilized mouse models of lung adenocarcinoma to firstly interrogate the tumor suppressive functions of RB and the therapeutic benefits of RB reactivation, and secondly evaluate the tumor suppressive abilities of frequently mutated chromatin regulatory genes. Using a synthetic gene switch to regulate Rb expression, we identified novel functions of Rb in restricting malignant progression, metastasis, and lineage infidelity. The loss of Rb results in an early progression to carcinomas without requiring MAPK amplification and leads to early metastases in conjunction with altered expression of lung lineage markers. Restoration of Rb expression however could revert these phenotypes, suggesting that reactivation of RB in advanced human lung adenocarcinomas may have therapeutic potential. In parallel, we examined the roles of the chromatin regulatory enzymes Brg1, Arid1a and Setd2 in lung adenocarcinoma tumorigenesis, using a novel CRISPR/Cas-expressing lentivirus to inactivate these genes in developing murine tumors. We identified a dramatic increase in tumor size upon the loss of Setd2, resulting from rapid cell proliferation, irrespective of p53 status. Further investigation identified increased mTORC1 signaling and mitochondrial activity in Setd2-deficient tumors, which sensitized tumors to inhibitors targeting these two processes. Furthermore, Setd2 loss led to global metabolic changes in SAM-dependent biosynthetic pathways, and Kras-driven tumors were extremely sensitive to methionine restriction, suggesting that Setd2 may suppress tumorigenesis in part by restricting SAM availability. This work has identified novel tumor suppressive functions for RB and SETD2 in lung adenocarcinoma, revealed potential therapeutic targets for lung adenocarcinoma treatment, and demonstrated the immense value of in vivo modeling to study tumor suppressor loss.