Oral squamous cell carcinomas can develop in various anatomical sites and has a variable biological behaviour. Tumor markers hold the promise of a revolution in disease diagnosis and therapeutic monitoring, provided that major challenges in genomics, proteomics and related disciplines can be addressed. The regulatory standards to be met by new measurement technologies for the clinical laboratory are very high. The measurements must not only be accurate, they must have a concrete medical implication. A more sophisticated understanding of the pathogenesis and the identification of better biological markers could provide useful information for predicting outcome and individualizing treatment.