Head and neck cancers are a heterogeneous group of malignancies accounting for approximately 600,000 new cases every year worldwide. Human papillomavirus (HPV) - related oropharyngeal cancers represent a new nosological entity for pathogenesis, molecular mechanisms, prognostic trend and therapeutic response. Several clinical trials have shown that HPV-positive/p16-positive cancer patients have a favorable prognosis demanding for de-escalation of current therapies. Comprehensive genomic analyses allowed to identify specific genetic alterations in targetable genes envisaging novel approaches to treat different subset of HPV-related and HPV-unrelated oropharyngeal cancers. Furthermore virus associated head and neck cancers may benefit from new developed immunotherapies targeting HPV E6 and E7 oncoproteins. We reviewed recent studies on the role of HPV infection in these cancers and present our current understanding of carcinogenic mechanisms providing possible novel approaches to cancer treatment.