Although relatively uncommon, oropharyngeal cancers are increasing in incidence despite declining prevalence of smoking and in direct opposition to a decreasing incidence of all other head and neck cancers. An epidemic of human papillomavirus (HPV)–associated oropharyngeal cancers seems to account for these incidence trends. Important demographic, behavioral, and prognostic characteristics define this unique population. Changes in prevention, diagnosis, evaluation, staging, and treatment are needed. This article summarizes the epidemiology and clinical behavior of HPV-associated oropharyngeal cancer and discusses evolving/potential paradigms of treatment. However, data are currently insufficient to change treatment paradigms for HPV-associated oropharyngeal cancer outside of a closely monitored clinical trial.