Because therapeutic efforts such as surgery, radiotherapy, and chemotherapy have only marginally improved the 5-year survival rate from cancers of the upper aerodigestive tract (including head and neck and lung cancers) over the past 2 decades, chemoprevention has become an important strategy in reducing the rates of incidence and mortality of these cancers. However, chemoprevention trials have been hampered by serious feasibility problems; they require large numbers of subjects and long-term follow-up for accurate determination of cancer incidence and they are very costly. Because the use of intermediate end points would reduce the duration and costs of these studies, biomarkers that could serve as such end points have recently become a subject of great interest. With the strengthening of the assumption that tumorigenesis is a multistep process of transformation from normal tissues to malignant lesions, there has been a great effort to examine each of these steps for genetic and/or phenotypic alterations that might be candidates for such biomarkers. These candidates include genomic markers, certain specific gene alterations, such as tumor suppressor genes, oncogenes, growth factors and their receptors, proliferation markers, and differentiation markers. In this review, we describe several genomic markers, including micronuclei, chromosomal alterations, and specific genetic markers, e.g., the ras gene family, erb B1, int-2/hst-1, and p53 tumor suppressor gene. We also review the proliferation markers, including proliferating cell nuclear antigen, and squamous cell differentiation markers, including keratins, involucrin, and transglutaminase 1. These biomarker candidates have the potential to be important adjuncts to the development of new chemopreventive agents and to the rational design of future intervention trials. However, we can not overemphasize that these markers need to be validated in clinical trials; only then can they replace cancer incidence as the sole end point for chemoprevention trials.