Oropharyngeal squamous cell carcinomas (OSCC) constitute about 5% of all cancers in the western world and the incidence and mortality rates of this tumor have shown little improvement over the last 30 years. Molecular targeted therapy, a promising strategy for the treatment of OSCC and other cancers, requires the understanding of specific molecular events of carcinogenesis and the different pathological, partly interrelated pathways. Extended knowledge of the prognostic or predictive value of molecular biomarkers in oropharyngeal cancer is necessary to allow a better characterization and classification of the tumor, improve the appraisal of clinical outcome and help to specify individual multimodal therapy with increased efficiency. This work affords an updated summary regarding recent data about tissue biomarkers in patients with OSCC, based on the six essential hallmarks of cancer described by Hanahan and Weinberg (Cell 100(1):57-70, 2000) providing the characterization of a malignant cell.