The association between human papillomaviruses (HPV) and oral cancer was initially suggested nearly 30 years ago by us. Today, the research interest of head and neck squamous cell carcinoma (HNSCC) has substantially increased. HPV-associated HNSCC is considered a distinct clinical entity with better prognosis than the classical tobacco and alcohol associated cancers. HPV 16 seems to be the main genotype present in HNSCC and it most probably utilizes the same pathways in epithelial cell transformation as established for genital cancer. High-risk HPV E6 and E7 target the well characterized cellular proteins p53 and Rb, respectively. In addition, several other cellular targets of E6 and E7 have been identified. This review gives an overview on the biology of HPV which aids in dissecting the role of HPV in head and neck carcinogenesis. It also summarizes the possible pathways involved in creating new tools for diagnosis and therapy of HPV-associated HNSCC.