Because they may be used as a quantifiable estimate of the extent of recent DNA injury, micronuclei, extrachromosomal fragments ofDNA, are among themost studied potential intermediate markers of cancer chemoprevention. Serial measurements of micronuclei frequency may be easily performed on scrapings from the oral cavity or on bronchial brushings. Assessment of micronuclei frequency and its response to chemopreventive agents has been incorporated into studies of upper aerodigestive tract and lung cancer chemoprevention. These studies have helped define the characteristics of micronuclei and have suggested a role for this test in future chemoprevention studies. Micronuclei frequency has been shown to be increased in the oral and bronchial mucosa of individuals with known carcinogen exposure and is higher at the site of the greatest carcinogen exposure, such as the site where tobacco quids are held, than in grossly normal-appearing mucosa. Treatment with chemopreventive agents leads to a reduction in micronuclei frequency. In oral leukoplakia studies, this effect followed treatment with 0-carotene, retinol, a-tocopherol, and 13-cis-retinoic acid. Themultistep process of epithelial carcinogenesis results from DNA damage and specific genetic events. That micronuclei reflect ongoing DNA injury suggests the hypothesis that long term suppression of cellular genotoxicity, as reflected by a reduction in micronuclei frequency, ultimately leads to a reduction in cancer incidence.