An association with HPV should be suspected in all oropharyngeal squamous cell carcinoma cases, particularly those originating from the base of the tongue and tonsils; in immunosuppressed HNSCC patients; and in cases with no or little-to-moderate exposure to tobacco and alcohol. HPV-positive HNSCCs and HPV-negative HNSCCs are distinct entities; they have different risk profiles and molecular profiles, and they respond differently to treatment. Therefore, their prevention and treatment may benefit from separate approaches. Antismoking campaigns and smoking-cessation programs have been successful in the prevention of HPV-unrelated HNSCC. The incidence of HPV-positive HNSCC may be reduced through enhanced public knowledge of the potential routes of HPV transmission, and by the prophylactic HPV vaccines currently widely available in the US for cervical cancer prevention (and which are now recommended for males to prevent genital warts).