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Recent whole-exome sequencing studies of numerous human cancers have now conclusively shown that theTP53tumor-suppressor gene is the most frequently mutated gene in human cancers. Despite extensive studies of theTP53gene and its encoded protein (p53), our understanding of howTP53mutations contribute to cancer initiation and progression remain incomplete. Genetically engineered mice with germline or inducibleTrp53somatic mutations have provided important insights into the mechanisms by which different types of p53 mutation influence cancer development.Trp53germline mutations that alter specific p53 structural domains or posttranslation modification sites have benefitted our understanding of wild-type p53 functions in a whole organism context. Moreover, genetic approaches to reestablish functional wild-type p53 to p53-deficient tissues and tumors have increased our understanding of the therapeutic potential of restoring functional p53 signaling to cancers. This review outlines many of the key insights provided by the various categories ofTrp53mutant mice that have been generated by multiple genetic engineering approaches.