Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and, despite advances in treatment, still represents a clinical challenge. Inactivation of one or more components of the p53 network is an extremely common event in human neoplasia. In HNSCC, disabling of p53 occurs in a high proportion of cases by mutation in the p53 gene, but other mechanisms of inactivation, such as the presence of human papillomavirus (HPV) and molecular abnormalities in other components of the pathway, are also recognised. The frequent changes occurring in the p53 pathway in HNSCC imply that molecular genetic and immunocytochemical analysis of this critical tumour suppressor network may be of diagnostic and prognostic utility in the clinical management of HNSCC. Further, these changes also provide targets for the development of novel therapeutic approaches to this increasingly common cancer, in which clinical cure for advanced disease remains an elusive goal.