The detection of Epstein-Barr virus (EBV) in nasopharyngeal carcinoma (NPC) has evolved over the last 40 years, transitioning from simple serological tests of latent viral infection to extremely sensitive measurements of the circulating tumor virome. Compared to the former, cell-free (cf) EBV DNA quantification is considered superior for population-based screening, and possesses additional advantages of clinical prognostication and surveillance for subclinical recurrences. However, despite its broad utility, the clinical value of cf EBV DNA for prediction of treatment response remains uncertain, and is currently being investigated in prospective clinical trials. These lessons from EBV and NPC have since been tested in another emerging viral-associated head and neck cancer that is linked to the human papillomavirus (HPV).