The human papillomavirus (HPV) has recently been identified as an important etiologic agent in the development of squamous cell carcinoma of the oropharynx. The HPV- associated cancers appear to have a different biology than the HPV-negative cancers, and affect a population that is more likely to be young, male, Caucasian, and nonsmoking. More importantly, however, is the recognition that patients with an HPV-associated oropharyngeal cancer have a distinctly better survival after treatment than those patients with HPV-negative tumors, although their prognosis is significantly worse if there is a history of tobacco abuse. HPV-associated oropharynx cancer should be recognized as a new biologic entity and studied separately from HPV-negative cancers in future clinical trials. The potential for disease prevention with the use of the current HPV vaccines is discussed.