Advanced head and neck cancer is a disease with poor prognosis. TNM staging is an inadequate prognostic indicator of individual response to evolving multimodal therapies. New markers have been studied in progressively more refined analyses. Even though their role in predicting response and prognosis of head and neck cancer is still under evolution, it is becoming clear that individual markers are inadequate in constructing a prognostically meaningful tumor profile for each patient. Rather the combined study of a number of well-characterized markers acting in unrelated cellular pathways may be much more successful in defining prognostic patient categories of greater utility than traditional TNM staging. Special attention should also be paid to the expression pattern and location of tumor markers within the biopsy specimen as these parameters also appear to influence prognostic significance.