The causative relationship between high-risk HPV and OSCC is well-established. HPV-associated OSCC represents a distinct disease entity compared to tobacco-associated ones. These virus-associated cancers continuously express the HPV E6 and E7 viral oncogenes even in advanced stages, and repression of viral oncogene expression can prevent the growth or survival of cancer cells. This finding raises the possibility that even late-stage HPV-associated OSCC can be cured by HPV-targeted approaches, such as medicines that interfere with the expression or function of viral oncoproteins, and therapeutic vaccines that elicit a cytolytic immune response to cells expressing these oncoproteins. The demonstration that high-risk HPVs are causally associated with a subset of OSCC has allowed the development of preventive and therapeutic strategies aimed at reducing the incidence and mortality of this disease. The better outcome of HPV-associated OSCC raises the question as to whether similar results can be achieved with less treatment. An important aim of novel approaches for favorable-prognosis, HPV-associated cancers will be minimization of devastating side effects of intensified treatment developed for poor prognostic subsets. Clinical trials are studying the potential for de-escalation of radiation therapy in HPV + OSCC in the setting of different chemoradiotherapy regimens. The role of cetuximab in HPV-associated OSCC needs to be explored in prospective clinical trials. This review summarizes the main events of HPV-induced carcinogenesis with an emphasis on the implications of these carcinogenic mechanisms on research, treatment and prevention of HPV-associated OSCC.