Head and neck cancers arise and progress through specific genetic alterations. Elucidation of these genetic changes has led to the development of a preliminary molecular progression model. Critical oncogenes and areas of chromosomal loss have been identified in a high proportion of squamous cell carcinomas. Oncogene mutations have given insight into the origin of these neoplasms and the fundamental cellular pathways that must be altered for progression. Further characterization of these genetic alterations will lead to improved molecular assays with important implications for diagnosis, prognosis, and therapy.