This is interactive panel presenting the most up-to-date evidence of the role of HPV in head and neck cancer incidence, treatment, and prognosis with a focus on how this impacts the practice of the general otolaryngologist. The latest evidence and guidelines for testing of HPV status in suspected malignancies of the upper aerodigestive tract will be reviewed. Updated evidence on the utility of HPV in the work up and management of the unknown primary neck mass will be emphasized. The impact on prognosis (and staging) will be discussed with a focus on recent controversy surrounding HPV status on prognosis for non-oropharyngeal subsites. Use of circulating tumor DNA (ctDNA) will be discussed as it relates to the initial diagnosis and ultimate surveillance of patients with oropharyngeal squamous cell carcinoma. Recommendations on how the clinician should converse with patients (and families) regarding the diagnosis will be highlighted while reviewing evidence on how this impact patient/partner sexual behavior. Vaccination recommendations will be bolstered with evidence from recent studies demonstrating no impact on sexual behavior of teens receiving the vaccine.