Carcinoma of the oropharynx is of squamous histology in over 90% of cases. Oropharyngeal squamous cell carcinoma (OSCC) displays significant heterogeneity in terms of etiology, biology, and clinical behavior. It has now become clear that a subset is initiated by infection with high-risk human papillomavirus (HPV) types, especially type 16. This review summarizes the epidemiology, clinical presentation, molecular pathogenesis, diagnosis, and therapy of OSCC, focusing on the HPV-associated cases; it also details the need for a better understanding of the molecular pathogenesis of the different types of OSCC in order to improve treatment.