Oral cancer is increasing in prevalence and its treatment is associated with high degree of morbidity and mortality. Thus, prevention of oral cancer is of utmost importance. Chemoprevention is the use of natural, synthetic, or biologic compounds to halt, reverse, or prevent the initial phases of carcinogenesis or the progression of neoplastic cells to cancer. This modality has been extensively researched in the last two decades for the prevention of oral cancer with the emergence of new information. Retinoids were the first chemopreventive agents to be tested in clinical settings. Since then, a number of new agents such as COX2 inhibitors, EGFR inhibitors, p53 targeted agents, thiazolidinediones and several natural agents have shown promise in oral cancer prevention. Chemopreventive trials in oral cancer tend to be long term studies and are thus challenging. This review article looks into the clinical evidence for the application of chemopreventive agents in clinical settings and also highlights the recent trends in oral cancer chemopreventive trials.