The article reviews the epidemiology, biology, virus detection, and management of HPV-associated head and neck cancer. It highlights the recent increase in oropharyngeal squamous cell carcinoma, particularly in white men under 50 who are non-smokers and non-alcoholics. The cancer is associated with human papilloma virus-16 (HPV16) infection, with risk factors including multiple oral and vaginal sex partners at a young age. The biology of HPV-related oropharyngeal cancer differs from tobacco-related cases, characterized by p53 degradation, Rb pathway inactivation, and p16 upregulation. HPV detection methods, including in situ hybridization and PCR, are commonly used, with p16 immunohistochemistry potentially serving as a surrogate marker. HPV-related oropharyngeal cancer is more responsive to chemotherapy and radiation therapy compared to HPV-negative cases. HPV16 is a prognostic marker for improved overall and disease-free survival but is not yet a predictive marker. The article discusses the need for further research on the natural history of oral HPV infection, the role of HPV vaccines, and the development of less morbid treatment regimens.The article reviews the epidemiology, biology, virus detection, and management of HPV-associated head and neck cancer. It highlights the recent increase in oropharyngeal squamous cell carcinoma, particularly in white men under 50 who are non-smokers and non-alcoholics. The cancer is associated with human papilloma virus-16 (HPV16) infection, with risk factors including multiple oral and vaginal sex partners at a young age. The biology of HPV-related oropharyngeal cancer differs from tobacco-related cases, characterized by p53 degradation, Rb pathway inactivation, and p16 upregulation. HPV detection methods, including in situ hybridization and PCR, are commonly used, with p16 immunohistochemistry potentially serving as a surrogate marker. HPV-related oropharyngeal cancer is more responsive to chemotherapy and radiation therapy compared to HPV-negative cases. HPV16 is a prognostic marker for improved overall and disease-free survival but is not yet a predictive marker. The article discusses the need for further research on the natural history of oral HPV infection, the role of HPV vaccines, and the development of less morbid treatment regimens.