Despite significant improvements in therapeutic protocols, head and neck squamous cell carcinoma (HNSCC) remains a major health problem worldwide. The 5-year post-therapeutic survival rate is among the lowest of the major cancers with loco-regional relapse being the main cause of death. Moreover, in most instances, the quality of life of the afflicted patient is severely compromised. The poor prognosis for HNSCC is primarily due to disease detection at advanced stages. Accordingly, development of early detection and preventive strategies are essential. Recent advances in our understanding of the molecular biology and etiology of HNSCC should facilitate development of improved intervention and therapeutic approaches. The present review discusses the potential role of such factors for developing preventive and early diagnostic strategies for HNSCC management. J. Cell. Physiol. 227: 467–473, 2012. © 2011 Wiley Periodicals, Inc.