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It is not a coincidence that the aerodigestive tract has proven such a fertile ground for the evaluation of chemoprevention. The incidence of second primaries and the concept of field cancerization made the need for prevention acute and showed the limitations of even the most curative of treatments. New and presumably less toxic agents are being evaluated; chemoprevention is being applied to asymptomatic populations at higher risk for lung, colon, breast, and other neoplasias. Biomarkers may be instrumental in rapid development of these new clinical applications, but much is still to be done. Yet unanswered is whether suppression of premalignant lesions will ultimately decrease cancer incidence. Survival in the second primary prevention trial has not thus far shown a significant improvement and toxicities were significant. Many questions remain in the study of chemoprevention; head and neck cancer provides a conducive model in which these answers might be found.