Human papilloma virus (HPV)-positive oropharyngeal cancer (OPC) is increasingly prevalent and has a favorable prognosis compared to HPV-negative OPC and other head and neck malignancies associated with smoking and alcohol. De-escalation of definitive therapy for HPV-positive OPC is an attractive strategy aiming to maintain oncologic efficacy while reducing short-term and long-term toxicities and improving quality of life. In this article, we outline approaches to de-escalation including use of alternative systemic therapies, reduction in dose of systemic therapy, and reductions in radiation dose and/or volume. We also highlight successes and cautionary outcomes from de-escalation studies and advocate for a personalized approach to future de-escalation trials in HPV-positive OPC.