Infection with human papillomavirus (HPV) is necessary for the development of cervical cancers, but a pathogenic role for these viruses in non-anogenital cancers has been unclear until recently. Epidemiological and laboratory evidence now warrant the conclusion that, in addition to tobacco and alcohol, HPV is a causative agent for some head and neck squamous-cell carcinomas (HNSCC). As with cervical cancer, HNSCC is a worldwide publichealth problem, with more than 500 000 incident cases every year. By contrast with cervical cancer, high-risk HPVs are not necessary for the development of all cases of HNSCC. This fact initially obscured the role of HPV, which is detected in only some HNSCC. However, research over the past several years has shown a strong and consistent association between high-risk HPV and a distinct subset of HNSCC. In some HNSCC, HPV DNA (overwhelmingly type 16) is present in primary and metastatic tumour-cell nuclei—in high copy-numbers, frequently integrated, and transcriptionally active. These HPV-associated HNSCC are characterised clinically by their location within the lingual and palatine tonsils of the oropharynx, their poorly differentiated histopathology, and their more frequent occurrence in non-smoking and in younger patients than in HNSCC not associated with