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This review focuses on oral cancer disease mechanisms and discusses ongoing research to identify molecular signatures or biomarkers for oral cancer. Other areas covered include the analysis, validation, and predictive value of these markers.During the past years, progress has been made in the oral cancer genetic markers field, which includes alterations of the p53 tumor suppressor protein, the inactivation of cyclin dependant kinase inhibitors (e.g. p16) and the overexpression of the epidermal growth factor receptor. Many of these markers are thought to have potential clinical interest, yet few of them are being used in a clinical setting for oral cancer management. The particular modifications that characterize each step of oral cancer progression can now be profiled by several high throughput discovery techniques. Genomic and proteomic studies of oral cancer tissues, plasma, and saliva of oral cancer patients, have allowed the identification of several promising cancer signatures.Important progress has been made in the molecular understanding of oral cancer and its application for diagnosis, prognosis and treatment. The increased efforts in translational research will result in earlier diagnosis of oral cancer, better knowledge of prognostic factors, and the development of targeted treatment regimens based on patients' clinical and biological characteristics at presentation.