Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma is a distinct tumor entity with clinical, epidemiologic, genetic, histologic, prognostic, and treatment differences from smoking- and alcohol-related head and neck squamous cell carcinoma. This is now well known by the pathology and medical community. What is not yet widely known is that several emerging variants of HPV-related carcinoma of the head and neck exist apart from the prototypical non-keratinizing morphology. Further, there is currently considerable variation in methodologies used and clinical scenarios in which to test for HPV-related head and neck squamous cell carcinoma, and no standard approach has emerged. In this article, we will review the morphology of prototypical HPV-related squamous cell carcinoma of the oropharynx and other HPV-related variants of head and neck carcinoma with an emphasis on their differential diagnosis, grade, and prognosis, as well as outline the current best practices for testing for HPV in head and neck carcinomas.