Results from epidemiological studies indicate that long-term intake of non-steroidal anti-inflammatory drugs, which inhibit cyclooxygenase (COX) enzymes involved in prostaglandin biosynthesis, reduces the risk of several forms of human malignancies. Expression of COX-2 in tumors is known to be associated with enhanced angiogenesis, suppression of host immunity, and tumor invasion. Genetic or pharmacological inhibition of COX-2 has been shown to protect against experimentally-induced carcinogenesis and to reduce the growth of xenografted tumors in animal models. A number of studies also revealed that COX-2 inhibition suppresses proliferation, metastatic potential, and other functions of cancer cell lines. Thus, it is conceivable that targeted inhibition of abnormally or improperly elevated COX-2 provides one of the most effective and promising strategies for cancer therapy. In this review, the involvement of COX-2 in the tumorigenesis of oral cancers and the potential mechanisms of tumor suppressive effects of COX-2 inhibition are discussed.