High-risk types of human papillomaviruses (HR HPV) play an important role in the etiology of a group of head and neck squamous cell cancers (HNSCC). This review is focused on epidemiological, molecular, and clinical aspects of HPV infection in head and neck cancer. High risk HPV DNA is being detected in a very different proportion of HNSCC with the highest prevalence in oropharynx. Patients with HPV-associated tumors are characterized by moderate tobacco and alcohol consumption. Some aspects of sexual behavior may represent a risk factor. Recently, it has been shown that HPV infection is spreading and the rising prevalence of HPV-positive tumors can probably be attributed to this epidemic. On molecular level the viral oncoproteins E6 and E7 were shown to be involved in oncogenesis. HPV-positive cancers have better prognosis and HPV status should be considered in clinical decision-making. The rising proportion of HPV-positive tumors underlines the importance of HPV vaccination also for the prevention of HNSCC.