This article focuses on squamous cell carcinomas of the larynx, pharynx and oral cavity which count nearly 90% of the head and neck squamous cell carcinomas (HNSCC). Individual susceptibility depends on an individually given genetic background and/or acquired conditions or factors elevating the risk of HNSCC including smoking, alcohol abuse, and improper oral hygiene. A key issue in HNSCC pathogenesis is their development within large preneoplastic fields of mucosal epithelium made up of genetically altered cells that are clonally related to the carcinoma. Other individual differences in development of HNSCC comprise infection with pathogenic microbes and oncogenic human papillomavirus (HPV) subtypes like HPV 16 (a strong risk factor mainly for oropharyngeal cancer). Interestingly, the presence of HPV 16 also goes in line with better outcome after therapy. Vaccination against HPV infection in children plays an increasing role in prevention strategies and probably also reduces the oncogenic risk for HNSCC.