Head and neck squamous cell carcinoma (HNSCC) represents 6% of all cancers. The overall 5-year survival rate for patients with this type of cancer is among the lowest of the major cancer types and has not improved dramatically during the last decade. The pathological staging, in particular the nodal stage, is the most important factor in HNSCC. The lack of progress in head and neck oncology emphasizes the importance of molecular genetic studies to define alterations that may correlate with tumor behavior. The molecular alterations observed in HNSCC are mainly due to oncogene activation and tumor suppressor gene inactivation, leading to deregulation of cell proliferation. These alterations include gene amplification and overexpression of oncogenes such as ras, myc, EGFR and cyclin D1, and mutations and deletions leading to p16 and TP53 tumor suppressor genes inactivation. This article reviews the molecular changes commonly observed in HNSCC. The biological function of these markers and the potential clinical application are discussed. Advances in the understanding of the molecular basis of HNSCC will help in the identification of new molecular markers that could be used for a more accurate diagnosis and assessment of prognosis and may open the way for novel approaches to treatment and prevention.