Cyclooxygenase-2 (COX-2) levels are increased in various tumors, particularly those involving the esophagus, stomach, breast, pancreas, lung, colon, skin, urinary bladder, prostate and head and neck. Nevertheless, the tumorigenic mechanisms of COX-2 overexpression still remain poorly understood and may include mechanisms that may act at different stages of the disease. Thus, the literature shows increasing evidence that overexpression of the COX-2 plays an important role in tumor growth and spread of tumors by interfering with different biological processes such as cell proliferation, cellular adhesion, immune surveillance, apoptosis, and angiogenesis. Furthermore, the expression of COX-2 might shed some light over the physiopathology and clinical behavior of tumors of the head and neck, including benign odontogenic neoplasms of the jaws with an aggressive behavior, such as keratocystic odontogenic tumors (KCOT). Ultimately, the research of molecular markers associated with the biological behavior of tumors will help to understand the underlying molecular mechanisms and to predict the clinical outcome, leading to the development of new therapeutic applications, such as molecular-targeted treatment and patient tailored therapy.