HPV is the most common sexually transmitted disease, but the overwhelming majority of individuals clear the infection. A small percentage of individuals develop persistence of oncogenic HPV types, especially HPV-16; and as a result, squamous cell carcinoma can develop in the tonsils and base of the tongue. Over 70% of oropharyngeal cancers are now thought to be associated with oncogenic HPV infection. Immunohistochemistry for p16 protein is often used as a surrogate marker for oncogenic HPV in the oropharyngeal tissues, although alternative HPV DNA testing methods are under intensive study. The clinical profile of patients with HPV-associated oropharyngeal cancer (OPC) differs quite notably from that of traditional head and neck cancer patients, and the prognosis for HPV-associated OPC is significantly better. As a result, experimental clinical trials are focused on de-intensification of therapies with the hope of preserving an improved long-term quality of life for these patients.