Patients with successfully treated upper aerodigestive tract (UADT) tumors commonly develop second primary tumors (SPTs). These tumors occur more often than chance would predict, arise in both the upper or lower aerodigestive tracts, are frequently preceded by leukoplakia, and are a major cause of treatment-related failure. Measures to control SPTs include primary prevention with tobacco and alcohol abstinence, surveillance endoscopy, and secondary chemoprevention. Chemoprevention is the administration of natural or synthetic substances to suppress or reverse the malignant process. Secondary chemoprevention of the UADT is the suppression or reversal of leukoplakia and/or SPTs. Classic antioxidant micronutrients such as retinoids, carotenoids, and certain other agents have been effective in nonrandomized and randomized clinical trials, but treatment is uncertain and recurrences common. These facts, coupled with recent harmful effects of beta-carotene in two clinical trials, stress the need for additional basic science, translational, and clinical research. Chemoprevention is a promising new technology, but is not currently standard therapy for the secondary prevention of UADT tumors.