The association of human papillomavirus with the development of head and neck squamous cell carcinomas has been better elucidated over the past 20 years. In this review article, we examine the role of the virus in the development of these tumors. We discuss the clinical and pathologic features of human papillomavirus-associated squamous cell carcinomas of the head and neck. Immunohistochemical findings and those of other ancillary techniques are also reviewed. We further review the prognosis and treatment of these tumors. Finally, a detailed discussion is provided regarding the differential diagnosis that must be considered when confronting these squamous neoplasms.