Chemoprevention trials in lung and upper aerodigestive tract (UADT) cancer are guided by the field cancerization hypothesis. Inhaled carcinogens place the entire epithelial lining at risk for the development of cancer. The hypothesis is supported by the occurrence of premalignant lesions, such as leukoplakia or squamous metaplasia, and multiple primary tumors within the field. The concept of carcinogenesis as a multistep process suggests the possibility of blocking or reversing the progression to invasive cancer with systemic treatment. A series of ongoing clinical trials will determine the efficacy of retinoid chemoprevention and will attempt to develop intermediate biomarkers. Biomarkers which reliably reflect progression towards cancer could be used to dramatically improve the efficiency of chemoprevention trials and also would aid in screening potential chemoprevention agents. Genomic biomarkers include non-specific estimates of ongoing DNA injury, such as micronuclei, as well as development of aneuploidy and alterations in oncogenes. A class of biomarkers of increasing importance assess proliferation and growth regulation, and include proliferating cell nuclear antigen (PCNA), TGF-beta, EGFR and retinoid receptors. Other markers, such as the blood group antigens, reflect differentiation and may be associated with the development of premalignant lesions. Preliminary data from several of these markers has suggested an association with carcinogenic exposures and premalignant lesions, but none of these markers either alone or in panels have yet been validated as a reliable surrogate for the development of invasive cancer.