Exposure of the oral cavity and oropharynx to human papillomavirus (HPV) often results in an asymptomatic, transient oral infection that is cleared by the body's immune system; however, a small percentage of these oral infections can persist in a dormant state. Depending on the HPV genotype, a persistent oral infection may lead to benign or malignant disease. High-risk HPV types 16 and 18, which cause most cervical and anal cancers, also are the cause of the rising rate of oropharyngeal squamous cell carcinoma (SCC) in the United States. This article focuses on the epidemiology, transmission, risk factors, and clinical presentation of HPV-associated oropharyngeal SCC, and provides an update on HPV vaccination in the context of the new head and neck cancer epidemic.