Despite improvements over the last decade, survival rates for head and neck squamous cell carcinoma (HNSCC) remain around 50% and variable. Recently, a subset of HNSCC has been shown to contain human papillomavirus (HPV) and the presence of HPV in tumors constitutes a prognostic marker of disease. HPV-DNA in these tumors (overwhelmingly genotype 16, a high-risk type also found in cervical cancer) is present at high copy numbers, frequently integrated, and often transcriptionally active. In comparison with HPV-negative tumors, however, HPV-positive HNSCCs are more likely to be located within the oral cavity/pharynx and diagnosed at a late stage. Based on the epidemiological evidence to date, it is reasonable to hypothesize that HPV-positive and -negative HNSCC represent different lineages formed through diverse, though overlapping, mechanisms of multistage tumorigenesis. The introduction of prophylactic and therapeutic HPV vaccines could have important implications for the prevention and control of a substantial fraction of HNSCC.