The article provides a comprehensive overview of TP53 mutations in human cancers, their origins, consequences, and clinical applications. TP53 mutations are the most frequent alterations in human cancers, with somatic mutations occurring in almost every type of cancer and germline mutations causing Li-Fraumeni syndrome. The article discusses the diverse types and positions of TP53 mutations, their structural and functional impacts, and their potential as prognostic and predictive markers. It also highlights the use of the IARC TP53 Database for data compilation and the Hupki mouse model for experimental studies. The article further explores the epidemiological, diagnostic, and therapeutic utility of TP53 mutations, emphasizing their complex biomarker status and the need for large-scale clinical trials to translate these findings into clinical practice.The article provides a comprehensive overview of TP53 mutations in human cancers, their origins, consequences, and clinical applications. TP53 mutations are the most frequent alterations in human cancers, with somatic mutations occurring in almost every type of cancer and germline mutations causing Li-Fraumeni syndrome. The article discusses the diverse types and positions of TP53 mutations, their structural and functional impacts, and their potential as prognostic and predictive markers. It also highlights the use of the IARC TP53 Database for data compilation and the Hupki mouse model for experimental studies. The article further explores the epidemiological, diagnostic, and therapeutic utility of TP53 mutations, emphasizing their complex biomarker status and the need for large-scale clinical trials to translate these findings into clinical practice.