Human papillomavirus (HPV) is a major causative agent of cervical cancers. Over the past several decades, increasing number of studies established strong association of HPV with a subset of head and neck squamous cell carcinomas (HNSCCs). In the present study, we reviewed evidence, including epidemiology, carcinogens, diagnosis, treatment, and pro-gnosis, showing that HPV-positive HNSCCs exhibit a variety of distinct characteristics for understanding tumor biology and improving cancer treatment.