Head and neck squamous cell carcinoma is ideally suited for chemoprevention efforts. Elucidation of molecular events underlying head and neck cancer has facilitated the development of preventive strategies. Landmark trials of 13-cis retinoic acid demonstrated that chemoprevention of head and neck cancer is indeed possible. New agents targeting specific molecular abnormalities contributing to the multifocal and multistep process of carcinogenesis have been identified. Innovative approaches to the study of chemoprevention, such as the use of biomarker intermediate end points, can select agents with particular promise for more definitive trials. However, barriers to progress in chemoprevention remain, including the validation of surrogate end point biomarkers and identification of safe and well-tolerated agents with the ability to delay carcinogenesis.