The overall incidence of HPV-positive oropharynx cancers is increasing in the United States. Deintensification treatment protocols for HPV-associated locally advanced oropharyngeal cancer are being investigated in ongoing clinical trials. Strategies under active investigation include reducing or using response-stratified radiation therapy (RT) dose, using RT alone versus chemoradiation, using less invasive surgical procedures such as TORS, using sequential systemic therapy/RT, and using immunotherapy and targeted therapy agents.