With a worldwide incidence of 263,900 cases and 128,000 deaths from oral cavity and lip cancer in 2008, squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers and a major cause of cancer-related deaths . SCCHN comprises a wide spectrum of neoplasms, such as cancers of the lip, oral cavity, larynx, pharynx and paranasal sinuses. National and international reports on cancer statistics on oral cavity and lip cancer, which often do not account for these other cancers, are therefore, likely to underestimate the magnitude of problems associated with SCCHN. Consistent with the high incidence of the disease, the economic consequence of managing SCCHN is also enormous; in the USA, the annual total direct and indirect cost of SCCHN is estimated to be approximately US$2 billion (2001 value) . In the USA, cancer of the oral cavity and pharynx presents with localized disease in 32% cases, whereas it is 47 and 16% present with regional and distant metastasis, respectively. The corresponding 5-year survivals for localized, regional and distant metastasis are 82, 57 and 35%, respectively. Although the 5-year survival has improved from 53% in 1975–1977 to 65% in 2002–2008 , this has mostly been observed in earlier disease stages. Outcomes in the setting of distant metastases are dismal, with a median survival of less than 1 year . Hence there is still scope for significant improvement in the management of these cancers. In this article, we discuss the molecular biology of SCCHN and the potential role of sorafenib.