There is currently sufficient evidence to conclude that human papillomavirus (HPV) plays a role in the pathogenesis of a distinct subset of head and neck squamous cell cancers (HNSCC), particularly tonsillar cancers. There is a strong and consistent association between high-risk HPV types, specifically HPV16, a known human carcinogen, and these distinctive oropharyngeal cancers with molecular characteristics indicative of viral oncogene function. Risk for HPV-HNSCC is increased by certain sexual behaviors after consideration of alcohol and tobacco exposure, consistent with an extensive literature that has established HPV infection as a sexually transmitted disease. Furthermore, exposure to HPV16 has been associated with increased risk for subsequent development of oropharyngeal cancer. Prophylactic and therapeutic vaccines targeted against the viral capsid components and oncoproteins will provide the ultimate evidence for a role for HPV in HNSCC, if demonstrated to be effective in the prevention or therapy of this disease. It is time for clinician scientists to translate knowledge of this newly recognized disease entity into potential applications for the prevention, detection, and treatment of HPV-HNSCC.