Squamous cell carcinomas of the head and neck belong to the most common cancers worldwide. Although they are in general on the decline, rising incidence rates have been reported for certain specific sites. In developed countries the impact of classical risk factors like tobacco and alcohol seems to decline, while the association with oncogenic papillomavirus infections, in particular in cancers of the oropharynx, is increasing markedly. The accumulation of genetic and epigenetic changes due to toxin exposure leads to inactivation of tumor suppressors or activation of proto-oncogenes, resulting in genetic instability and malignant transformation in non-papillomavirus-related cancer. Papillomavirus-related cancers infrequently contain genetic alterations and are caused by deregulation of the cell cycle, senescence and apoptosis induced by viral oncoproteins. Detection of oncogenic papillomavirus infections may be basis for further classification of head and neck squamous cell carcinoma and could be a key in differential treatment modalities for subsets of head and neck cancer in the near future.