Head and neck squamous cell cancer is the sixth most common cancer in the world. Despite advances in combined modality therapy, poor outcomes continue to be observed in the form of locoregional recurrence, metastasis, and development of second primary tumors. As tumors vary in their molecular and genetic etiology and because often there is already deregulation at the molecular level in otherwise histopathologically normal tissue, risk stratification using clinical and pathologic criteria alone has proved to be inadequate. In this article, the reader will gain an appreciation for the current advances in biomarker discovery using advanced technology and data interpretation in microarray analysis and proteomics. In addition, other molecular targets, aside from epidermal growth factor receptor, are discussed in the context of their promising role in predicting recurrence, response to therapy, survival, and overall prognosis.