The focus of this book chapter is to discuss the role of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) and Epstein-Barr virus (EBV) in nasopharyngeal carcinoma (NPC). We have summarized the main events of HPV & EBV life cycle, potential mechanisms of HPV- or EBV-mediated carcinogenesis, and the implications of HPV and EBV in head and neck cancer, with an emphasis on disease diagnosis, prognosis, and therapeutic treatment. The potential of proteomics for studying these virus-associated cancers has also been discussed. A mechanistic understanding of HPV-associated HNSCC or EBV-associated NPC would require profound analysis of these tumors using advanced molecular analysis technologies, which will then facilitate the development of preventive and therapeutic strategies for these diseases.