HPV-positive (HPV+) oropharyngeal carcinoma (OPC) continues to increase in incidence across the globe. Multimodality treatment offers a high likelihood of cure in HPV+ OPC but comes at a high cost of treatment-related morbidity. As a result, de-escalation of treatment to limit toxicity without compromising high cure rates has emerged as a major trend in head and neck cancer clinical research. Primary surgery with minimally invasive resection of the primary disease may allow for the elimination of chemotherapy and decrease radiation dose intensity. Primary dose-reduced radiation, with or without systemic therapy, is also under study, as is replacing concurrent cisplatin with newer systemic agents. Numerous institutional series and phase II trials have been presented, and the first generation of de-escalation randomized phase III trials have now been published. The various combinatorial multimodality strategies to achieve less intensive and toxic therapy are many. Has the time come for de-escalation as a standard approach to HPV+ OPC? The pros and cons, as well as the best approaches for de-escalated treatment of HPV+ OPC, are debated here.