Human papillomavirus (HPV) infection is the most common sexually transmitted disease. It also contributes significantly to infection-associated human malignancies, including cervical, anal, penile, vaginal, and vulvar cancer as well as a subset of head and neck squamous cell carcinoma (HNSCC). Despite our extensive knowledge on the role of HPV in the etiology of cervical cancer, cervical cancer screening, prevention, and clinical management, we have just begun to appreciate the role of HPV in the tumorigenesis of HNSCC. In this paper, we will review our current knowledge on the natural history of oral HPV infection in the general population, risk factors for oral HPV infection, the presence of novel HPV types infecting oral cavity, limitations of existing methods for oral HPV detection and its application in the clinical setting. Finally, we will also discuss the role of HPV vaccine in preventing HNSCC.