Over the last two decades, it has been recognized that head and neck cancers, primarily in the oropharynx, can be a distinct entity that is causally related to human papilloma virus (HPV). Fakhry et al. (1) established in 2008 that such tumors have a strikingly better prognosis with improved responsiveness to chemotherapy as well as chemoradiotherapy and favorable survival rates. Since then, new studies have contributed to our increased understanding of this new entity, ranging from a detailed understanding of the genetic fingerprint and risk modifiers such as smoking to successful early attempts to personalize therapy with de-escalation in the definitive intent treatment setting and specific evaluation of targeted therapies in this patient population. This Commentary seeks to summarize the state of the art of our understanding of HPV-associated head and neck cancers that has emerged since the publication of seminal findings by Fakhry et al.