Cancers of the aerodigestive tract are a major cause of worldwide morbidity and mortality. Long term survival rates for these epithelial cancers have not improved substantially in the past 20 years despite intensive efforts to improve the prevention and therapy of these diseases. Therefore, new approaches are needed. One new investigative approach is chemoprevention, the chemical prevention of cancer. Chemoprevention studies in the upper aerodigestive tract have focused on the reversal of premalignant lesions and the prevention of second primary tumors. These chemoprevention efforts have resulted from an understanding of the multistep nature of epithelial carcinogenesis and the diffuse epithelial injury that results from carcinogen exposure. Ongoing research efforts are attempting to define these processes. The interaction between carcinogen exposure and host susceptibility in the development of cancers of the aerodigestive tract is being evaluated (e.g., with an assay of chromosomal sensitivity to the clastogen bleomycin). This review discusses several new aspects of the epidemiology, biology, and chemoprevention of aerodigestive tract carcinogenesis.