Head and neck cancer is the sixth most common cancer worldwide. The large majority are squamous cell carcinomas (HNSCC) that develop in the mucosal linings of the upper aerodigestive tract. These tumors develop either by exogenous carcinogen exposure (smoking, alcohol drinking) or by human papillomavirus (HPV) infection, particularly those in the oropharynx (OPSCC). HPV-positive (HPV+ve) and HPV-negative (HPV-ve) OPSCC are considered different disease entities. HPV+ve tumors are different at the molecular level and likely as a consequence have a much more favorable prognosis than HPV-ve tumors, despite their generally advanced stage at presentation. In general, HNSCCs develop in precancerous mucosal changes, and the apparent lack of precancerous HPV+ve mucosal changes is therefore remarkable. In this Chapter, head and neck carcinogenesis is discussed and the molecular differences between HPV+ve and HPV-ve tumors are outlined.