As a tumour suppressor gene, the inactivation of p53 induces the development of numerous human cancers. Mutations of p53 have been implicated in the pathogenesis of head and neck squamous cell carcinoma (HN-SCC) at a high incidence. In premalignant lesions and in situ carcinomas, p53 overexpression is not exclusively restricted to neoplastic cells, but frequently affects the normal appearing keratinocytes adjacent to p53 positive neoplasms or present in dysplastic areas. These results suggest that as contributors to the early phases of HN-SCC development, p53 alterations may be excellent biomarkers that indicate the predisposition of a particular oral cavity premalignant lesion toward malignancy. In most cases, the p53 overexpression status of a tumour metastasis is identical to that of a primary tumour, indicating that a p53 mutation precedes metastatic spread. In patients with multiple primary tumours, multiple foci of p53 overexpression are observed in epithelia distant from the tumour. So the expression of p53 in normal epithelium would indicate an increased risk for transformation to second or third primary cancers. Distinct p53 mutations in different primary tumours of the same patient indicate that these cancers arise as independent events; these results support the existence of multifocal polyclonal processes. Regardless of the aforementioned results that support p53 as a valid tumour biomarker, most studies have shown no relationship between the expression of p53 and clinical and histopathological parameters. The role played by p53 mutations in the progression and vital prognosis of HN-SCC has not yet been demonstrated.