Lung and head and neck cancers result from a multistep process involving activation of oncogenes and inactivation of tumor-suppressor genes. These two processes share common features and molecular players, while their corresponding clinical entities are both triggered by the tobacco carcinogens. In many cases, the molecular abnormalities associated with these multi-step and multi-focal processes can be found in pre-malignant lesions and normal tissue. The growing knowledge of the molecular basis of lung and head and neck carcinogenesis allows to better selecting molecular alterations that can be modulated by molecular targeted agents either in a curative or in a chemopreventive approach.