Mutant p53, a protein derived from mutations in the TP53 gene, has been shown to not only lose its tumor-suppressive functions but also gain novel activities. These neomorphic p53 proteins can significantly alter tumor cell behavior through interactions with other proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 can confer unique activities, offering insights into the mutagenic events driving tumor progression. This review discusses the mechanisms by which mutant p53 exerts its cellular effects, focusing on the mutant p53 transcriptome, and the biological and clinical consequences of its gain of function. The TP53 gene, located on chromosome 17p13.1, is the most frequently mutated gene in human cancer, with over half of all tumors exhibiting mutations at this locus. Initially, p53 was considered a proto-oncogene, but subsequent findings revealed its role as a tumor suppressor. The discovery of p53 as a proto-oncogene was challenged by evidence showing that p53 mutations could promote tumor growth. The concept of mutant p53 gain of function has emerged to explain these contradictory findings, suggesting that certain p53 mutants may have oncogenic roles in tumorigenesis. Mutant p53 can exert oncogenic effects through various mechanisms, including interactions with other proteins and regulation of novel target genes. These interactions can lead to altered transcriptional programs, promoting tumor growth. Mutant p53 can also interact with transcription factors such as NF-Y, Sp1, and Ets-1, enhancing their activity and contributing to tumor progression. Additionally, mutant p53 can bind to DNA structural motifs, such as matrix attachment regions (MARs), which may influence its transcriptional activity. The mutational spectrum of TP53 reveals "hot spot" mutations that occur at a higher frequency than expected, suggesting a selective advantage for these mutations. These mutations can be classified as either conformational or DNA contact mutants, with different effects on p53 function. The stability of mutant p53 in tumors is influenced by its ability to resist degradation, often leading to high levels of mutant p53 in tumor cells. The presence of mutant p53 can have significant clinical implications, as certain mutations are associated with poor prognosis in various cancers. Understanding the role of mutant p53 in tumor biology is crucial for developing targeted therapies. The diversity of mutant p53 proteins and their interactions with other cellular components highlight the complexity of p53's functions in cancer. As research continues, the identification of specific mutant p53 response elements and the development of strategies to target mutant p53 will be essential for improving cancer treatment outcomes.Mutant p53, a protein derived from mutations in the TP53 gene, has been shown to not only lose its tumor-suppressive functions but also gain novel activities. These neomorphic p53 proteins can significantly alter tumor cell behavior through interactions with other proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 can confer unique activities, offering insights into the mutagenic events driving tumor progression. This review discusses the mechanisms by which mutant p53 exerts its cellular effects, focusing on the mutant p53 transcriptome, and the biological and clinical consequences of its gain of function. The TP53 gene, located on chromosome 17p13.1, is the most frequently mutated gene in human cancer, with over half of all tumors exhibiting mutations at this locus. Initially, p53 was considered a proto-oncogene, but subsequent findings revealed its role as a tumor suppressor. The discovery of p53 as a proto-oncogene was challenged by evidence showing that p53 mutations could promote tumor growth. The concept of mutant p53 gain of function has emerged to explain these contradictory findings, suggesting that certain p53 mutants may have oncogenic roles in tumorigenesis. Mutant p53 can exert oncogenic effects through various mechanisms, including interactions with other proteins and regulation of novel target genes. These interactions can lead to altered transcriptional programs, promoting tumor growth. Mutant p53 can also interact with transcription factors such as NF-Y, Sp1, and Ets-1, enhancing their activity and contributing to tumor progression. Additionally, mutant p53 can bind to DNA structural motifs, such as matrix attachment regions (MARs), which may influence its transcriptional activity. The mutational spectrum of TP53 reveals "hot spot" mutations that occur at a higher frequency than expected, suggesting a selective advantage for these mutations. These mutations can be classified as either conformational or DNA contact mutants, with different effects on p53 function. The stability of mutant p53 in tumors is influenced by its ability to resist degradation, often leading to high levels of mutant p53 in tumor cells. The presence of mutant p53 can have significant clinical implications, as certain mutations are associated with poor prognosis in various cancers. Understanding the role of mutant p53 in tumor biology is crucial for developing targeted therapies. The diversity of mutant p53 proteins and their interactions with other cellular components highlight the complexity of p53's functions in cancer. As research continues, the identification of specific mutant p53 response elements and the development of strategies to target mutant p53 will be essential for improving cancer treatment outcomes.