Squamous cell carcinoma of the head and neck is one of the most common human cancers with an unchanged high rate of mortality despite improved diagnostic and therapeutic methods of the past twenty years. Latest advances of molecular biological methods contributed to the understanding of the multistep process of carcinogenesis. Genetic instability, dysregulation of cell cycle and apoptosis as well as changes of oncogenes and tumor suppressor genes are involved in carcinogenesis. So far, molecular markers do not fulfill the desired requirement of clinical relevance concerning early detection of cancer, estimation of prognosis and individualized therapy regimens in potential risk patients. With the establishment of the UICC TNM staging system first prognostic statements were made possible, which showed a positive correlation between tumor stage and prognosis. There is, however, a need of clinical and/or molecular parameters that reliably predict individual prognosis and results of individualized therapy. We discuss parameters that have been associated with prognosis of head and neck squamous cell carcinoma so far.