Human papillomavirus (HPV) associated oropharyngeal carcinoma is currently the most frequently diagnosed head and neck cancer in the United States. Due to the generally high cure rates with standard therapies, de-intensification strategies are being explored to reduce acute and long-term side effects. For patients treated with definitive chemoradiation, unselected de-escalation has shown worse progression-free survival compared to standard therapy. Concurrently, surgical management is becoming more prevalent, and adjuvant de-escalation appears promising. Further research is required to identify optimal candidacy for adjuvant de-escalation and to understand the relationship between dose and volume de-escalation. Biomarkers such as ctDNA may assist in candidate selection, but validation and alignment with pathological criteria are necessary.