Human papilloma virus (HPV) related head and neck cancer is rising in prevalence, preferentially affecting young patients and imparting long term toxicities. Despite this, there are no screening tests or clinical biomarkers for treatment monitoring. HPV circulating tumor DNA (HPV ctDNA) represents a novel circulating biomarker which may provide real-time assessment of tumor response to therapy and recurrence. Early work suggests the promise of this assay as a predictive biomarker in numerous clinical settings, namely risk of recurrence after chemoradiation in locally advanced disease. Advancement of these findings to the clinic will require a collaborative effort in the field, including technical harmonization of assay testing characteristics, understanding of the normal kinetics in patients being treated with standard of care therapies, and appropriately designed phase III trials prior to implementation in the clinic. If successful, HPV ctDNA has the potential to revolutionize clinical trial treatment paradigms and transform patient care.