The tobacco-related cancers that I treat, study and research, lung and head and neck cancer, account for 25% of all cancer related deaths in the United States. Our research has focused on three major areas: • The establishment of a molecular prognostic model for early stage non-small-cell lung cancer focusing on perturbations in retinoid signaling with examinations of downstream events as well as epigenetic phenomena. • The development of novel molecularly targeted strategies for the treatment of various stages of lung and aerodigestive cancer from pre-malignancy through advanced stage disease, including retinoids, rexinoids, oncolytic adenoviruses and farnesyl transferase inhibitors. • The conduct of multi-center, translational, national priority trials targeting the chemoprevention of those patients at highest risk for cancer development: those individuals who have manifested a prior malignancy and been successfully treated. Our integrated research program includes exploration of the mammalian target of rapamycin (mTOR) axis proteins and their importance in prognosis in lung cancer, translating these biological findings into therapeutic advances in lung cancer patients. The program also targets LKB1, a tumor suppressor gene known to be inactivated or mutated in lung cancer, tubulin acetylation through exploring the synergy between taxanes and farnesyl-transferase inhibitors, and the 14-3-3 proteins, key regulators of the mTOR axis (especially Akt). Our ultimate goal is to expand the therapeutic arsenal for lung cancer by enhancing individualized therapy using existing agents and to effectively develop novel targeted agents such as the mTOR inhibitors, farnesyl transferase inhibitors, and 14-3-3 inhibitors in lung and aerodigestive cancers.