The process of bronchial carcinogenesis is characterized by accumulated genetic abnormalities which ultimately lead to malignant transformation of bronchial epithelial cells, followed by invasion and metastasis. One of the most common and consistent of these genetic lesions is inactivation of the p53 tumor suppressor gene by mutation or deletion. The frequency of p53 alterations in lung cancer is highest in those subtypes of bronchial carcinomas that are most consistently associated with smoking, especially SCLC and squamous cell carcinomas. The frequency is lower in adenocarcinomas, in which the association with smoking, although present, is not as strong. The frequency of p53 abnormalities is higher in patients with greater cumulative tobacco exposure. Tobacco-specific carcinogens, in particular BPDE, cause a unique spectrum of p53 mutations, quite distinct from those found in cancers that are not associated with smoking. This characteristic genetic "signature" may persist even decades following smoking cessation. The prognostic significance of p53 mutations in lung cancer is not entirely clear despite the multitude of clinical studies that have been carried out. Nevertheless, the majority of clinical studies suggest that lung cancers with p53 alterations carry a worse prognosis. Furthermore, those tumors with mutant p53 may be relatively more resistant to chemotherapy and radiation. An understanding of the role of p53 in human lung cancer may lead to more rational targeted approaches for treating this disease. For example, the observation that the introduction of wild-type p53 into lung cancer cells with mutant or deleted p53 may reverse the malignant phenotype despite the presence of multiple other genetic abnormalities (14) suggests that replacement of this gene may be an effective clinical strategy. Preclinical and early clinical studies indicate that this is a promising approach, but clearly more effective means of gene delivery to the tumor cells are required (127-129), as discussed elsewhere in this volume.