Purpose of review: High-risk human papillomaviruses (HPVs) are implicated in the development of a subset of head and neck squamous cell cancers (HNSCCs), especially those arising from the lingual or palatine tonsils. HPV-associated HNSCCs represent a different disease entity from those associated with the traditional risk factors of tobacco and alcohol use. The demonstration that HPV is causally associated with a subset of HNSCC has tremendous clinical and research implications.

Recent findings: In recent years, there has been an increase in the annual incidence of HPV-related HNSCC in the United States and Europe. It has now become clear that a subset of HNSCC is a sexually transmitted disease with distinct pathogenesis and clinical/pathological features. HPV-associated HNSCCs have a better prognosis compared with stage-matched non-HPV-related HNSCC in the majority of studies. Research efforts are now focusing on deintensification of treatment to reduce treatment-associated morbidity. HPV-targeted therapies are under investigation.

Summary: The increasing incidence of HPV-related HNSCC has led to the development of novel research strategies in HNSCC. This review summarizes the epidemiology, clinical presentation, molecular pathogenesis, diagnosis, and therapy of HPV-associated HNSCC; it also summarizes how a better understanding of the molecular pathogenesis of HPV-associated HNSCC is expected to change treatment.