Squamous cell carcinoma of the oropharynx (OPC) consists of human papillomavirus (HPV)-negative disease caused by tobacco and alcohol use, and HPV-positive disease caused by the sexually transmitted infection HPV. These entities have unique but overlapping risk factors, epidemiologic trends, staging systems, and survival outcomes. HPV-positive tumor status confers a significant survival benefit compared with HPV-negative disease. OPC treatment entails a combination of surgery, radiation, and chemotherapy. Ongoing trials will determine whether treatment of HPV-related disease may be safely deintensified to decrease morbidity. Emerging HPV-related biomarkers are under study as tools to inform screening, diagnosis, treatment, and surveillance for HPV-positive OPC.