Changes in the p53 gene is one of the most common genetic changes associated with cancer, being implicated in a wide range of tumour types. In many types, more than half of the tumours are p53+. Often p53 positivity is correlated with high grade lesions (e.g., carcinoma of breast, prostate and bladder, malignant lymphoma) and poor prognosis. A few tumour types are characterised by strong p53 expression in most cases, e.g., uterine papillary serous carcinoma. In many tumour types (e.g., malignant lymphomas), p53 appear to have prognostic significance , but the data are often conflicting. In dysplastic lesions, e.g., in Barrett's esophagus, p53 expression increases the risk of carcinoma. p53 may be helpful in differentiating between certain reactive and neoplastic lesions, e.g., reactive urothelial changes (patchy and weak) v. urothelial neoplasia (~60% pos.); reactive mesothelial proliferation (~10% pos.) v. malignant mesothelioma (~60% pos.). p53 positivity is a parameter in the identification of tubal intraepithelial carcinoma associated with pelvic serous carcinoma. Tonsil and appendix are the most recommendable external positive and negative tissue controls. As a guideline for an accurate p53 IHC test more than 20% of germinal centre B-cells must show a weak to moderate nuclear staining reaction, while less than 10% of the mantle zone B-cells should be demonstrated in tonsil. In appendix, dispersed epithelial cells in the basal parts of the crypts must show a weak to moderate nuclear staining reaction, while the luminal epithelial cells must be negative. In addition, it has to be emphasized, that stromal cells, lymphocytes and endothelial cells in the clinical samples are essential as internal positive tissue controls especially for carcinomas with TP53 mutations causing absence and loss of p53 expression in the tumour cells.