Despite advances and improvements in diagnosis and treatment of upper aerodigestive tumors including head and neck and lung cancers, the overall survival rate of these patients remains poor. Prevention, early diagnosis, and novel therapy are under active investigation to improve the outcome of the diseases. In particular, chemopreventive strategy is a novel approach to reduce the invasive tumors by reversing the premalignant lesions with certain differentiating agents (i.e., retinoids). To conduct effective chemopreventive trials, there has been a great surge of interest in defining the biomarkers associated with the specific stages of the carcinogenesis and with intermediate end points during the therapy. Carcinogenesis in the upper aerodigestive tract has been explained by two theories, field cancerization and multistep process. The driving forces behind these processes are noted by accumulated genetic abnormalities in the entire epithelium of the airway. These genetic abnormalities include chromosome abnormalities, specific gene alterations (i.e., ras gene family, tumor suppressor genes, growth factors and their receptors), and proliferation and differentiation markers. These biomarkers are herein described in this review article.