A chemopreventive approach to cancers of the upper aerodigestive tract (including those of head and neck and lung) to reduce the incidence and mortality rates for these cancers has become an important strategy because therapies such as surgery, radiation, and chemotherapy have only marginally improved the five-year survival rate over the last two decades. However, chemopreventive trials have been hampered by serious feasibility problems, including high cost, the requirement of large numbers of patients, and long-term follow-up necessary to determine cancer incidence, which served as the study end point. Thus, the use of biomarkers, the identification of which would serve as an intermediate end point of the study has recently emerged as a subject of great interest. To try to understand the process of tumorigenesis from normal tissues through the premalignant tissue stage to malignant lesions, there has recently been a search for genetic and/or phenotypic changes that qualify as candidates for biomarkers. These candidates include genomic markers, certain specific genetic markers (such as oncogenes, growth factors and their receptors, and tumor suppressor genes), cell proliferation markers, and cell differentiation markers. This review covers genomic markers (including micronuclei and specific chromosomal alterations) and specific genetic markers (such as the ras gene family, the myc family, erb B1, int-2/hst-1, and the p53 tumor suppressor gene). As a consequence of genetic alteration, we also reviewed cell proliferation markers such as proliferating cell nuclei antigen (PCNA) and the squamous cell differentiations markers, including keratins, involucrin, and transglutaminase 1. These biomarker candidates are important adjuncts to the development of the new chemopreventive agents and to the rational design of future intervention trials. However, it should be emphasized that these biomarkers must first be validated in clinical trials; only then can they replace cancer incidence as the sole end point in chemoprevention trials.