Oral cancer is challenging for clinicians due to its high mortality and increasing incidence rate. Cyclooxygenase-2 (COX-2) is extensively expressed in oral cancer and oral premalignant lesions and seems to be enhanced specifically in high-risk oral lesions. Mounting evidence suggests that these inhibitors may represent a promising approach for chemoprevention or treatment of oral cancer. This review reports on Medline and PubMed literature searches of published articles from 1995 to 2003. Our purpose is to provide a comprehensive examination and discussion of the potential role of COX-2 in oral cancer development and the use of COX-2 inhibitors for oral cancer chemoprevention or treatment. The data in the literature strongly indicate that COX-2 is significantly upregulated in oral cancer and premalignant lesions, and we believe that inhibition of COX-2 would suppress development of oral lesions by affecting several pathways of oral carcinogenesis. Therefore, the COX-2 inhibitors should be investigated as a new treatment, particularly new chemoprevention agents, for patients who are at high risk for developing oral cancer.