The incidence of oropharyngeal cancer (OPC) related to infection with human papillomavirus (HPV) is rising, making it now the most common HPV-related malignancy in the United States. These tumors present differently than traditional mucosal head and neck cancers, and those affected often lack classic risk factors such as tobacco and alcohol use. Currently, there are no approved approaches for prevention and early detection of disease, thus leading many patients to present with advanced cancers requiring intense surgical or nonsurgical therapies resulting in significant side effects and cost to the health-care system. In this review, we outline the evolving epidemiology of HPV-related OPC. We also summarize the available evidence corresponding to HPV-related OPC prevention, including efficacy and safety of the HPV vaccine in preventing oral HPV infections. Finally, we describe emerging techniques for identifying and screening those who may be at high risk for developing these tumors.