The incidence of HPV-related head and neck carcinomas is rising in the United States, with the greatest increase among middle-aged white men. In fact, more than 95% of oral cancers are squamous cell carcinomas, a type that is most closely linked to high-risk HPV. The urgent need to understand HPV's impact on head and neck cancer patients is driving the need for a new evidence-based clinical practice guideline just released by the College of American Pathologists (CAP) and available in early online release from the Archives of Pathology & Laboratory Medicine (http://capatholo.gy/2AUcwbG). In this CAPcast, Dr. William C. Faquin, a pathologist from Massachusetts General Hospital, discusses the significance of these guidelines and how clinicians and pathologists can best implement them. Visit CAP.org for more resources on how pathologists can implement these guidelines: http://capatholo.gy/2BMfPoX.