Human papilloma virus (HPV)-positive head and neck cancer (HNC) is a relatively newly described type of squamous cell carcinoma that exhibits different biological features and response to therapy from its HPV-negative counterpart. The increased incidence of HPV-positive cancers and their distinctive response to therapy have introduced the need for a new approach in HNC management. The prevalence of molecular HPV markers in oropharyngeal versus non-oropharyngeal HNC showed that the probability of oropharyngeal cancer being HPV-related is fivefold higher than for other HPV-positive HNCs. This chapter tackles the radiobiological differences among HPV-related HNCs as well as the clinical implications of these disparities. Accurate testing for high-risk HPV patients is critical for adequate patient stratification, thus for personalised treatment planning and delivery. Other risk factors, such as smoking history, play an important role in further stratification. A new staging system for HPV-related oropharyngeal squamous cell carcinoma and the development of highly specific molecular markers to predict treatment response are required for optimal outcome.