During the past decade and a half, the most common cause of oropharyngeal squamous cell carcinoma (OPSCC) has shifted from tobacco and alcohol to the human papillomavirus (HPV). HPV-driven p16-positive OPSCC and tobacco-related OPSCC differ in their underlying molecular and genetic profiles, socioeconomic demographics, and response to treatment. HPV-related OPSCC tends to occur in younger patients and has a significantly better response to treatment and excellent prognosis. The stark contrast in prognosis-with around 90% overall 5-year survival for HPV-related p16-positive OPSCC and 40% for non-HPV-related p16-negative OPSCC-has prompted major changes in the eighth edition of the staging manual of the AJCC (American Joint Committee on Cancer). The past 10-15 years have also witnessed major advances in surgery, radiation therapy (RT), and systemic therapy. Minimally invasive surgery has come of age, with transoral robotic procedures and laser microsurgery. Intensity-modulated RT (IMRT) and more recently proton-beam RT have markedly improved the conformity of RT, with an ability to precisely target the cancer and cancer-bearing regions while sparing normal structures and significantly reducing long-term treatment-related morbidity. Progress in systemic therapy has come in the form of immunotherapy and targeted agents such as cetuximab. Owing to the better prognosis of HPV-driven OPSCC as well as the morbidity associated with treatment, de-escalation of therapy via multiple strategies is being explored. The article reviews the advances in diagnosis and multidisciplinary management of OPSCC in the HPV era.©RSNA, 2019.