Increasing emphasis has been placed on chemo-prevention as understanding of the genetic and molecular events of carcinogenesis has evolved. More than 1000 compounds that inhibit cancer development in vitro or in animal models have been identified, and active research is under way to determine which of these agents will be both effective and nontoxic in human beings. Currently, 13-cis-retinoic acid is the most studied chemopreventive agent against head and neck cancers. Unfortunately, this vitamin A derivative has significant clinical toxicity, which limits its utility in a practice setting. The efficacy of the retinoids, however, has stimulated efforts to find other chemopreventive compounds that are both effective and non-toxic. This review discusses head and neck premalignancy, chemoprevention strategies, retinoids, and several other classes of chemopreventive agents with potential efficacy against head and neck premalignancy.