As outlined by Leslie Kim and colleagues in this issue of ONCOLOGY, almost 650,000 new cases of head and neck cancer are identified and approximately 350,000 individuals die from this disease worldwide each year. Most cancers of the head and neck are squamous cell carcinomas and originate from one of five major sites: oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx. Traditionally, tobacco smoking and alcohol consumption have been considered to be the main risk factors for head and neck squamous cell carcinoma (HNSCC) and, thus far, most prevention strategies and public health messages have focused on these two factors. However, as described in the review by Kim et al., there is increasing evidence that, independent of tobacco and alcohol exposure, oral human papillomavirus (HPV) infection is a major risk factor for a specific subset of HNSCCs. We agree with the authors that this is an important public health concern, especially given the increasing prevalence of HPV infection in the US and Western Europe and our limited knowledge about the natural history of oral HPV infection. Here we summarize the role of HPV in HNSCC and discuss clinical implications.