Manipulation of the mouse genome allows emulation of the genetic defects that give rise to human cancers and evaluation of the cooperating nature of different mutations in the transformation of distinct cell types. Here we review the generation of mice with specific missense mutations in p53 (TP53) and disruption of the p53 pathway by deletion of p53 inhibitors. Missense mutations in the DNA binding domain result in viable mice with gain-of-function and dominant negative phenotypes. Loss of either of the p53 inhibitors mdm2 or mdm4 gives rise to a p53-dependent embryonic lethal phenotype. A cell can thus tolerate the absence of p53 function but not excess p53 function, a characteristic that is being exploited in the treatment of human cancers. Hum Mutat 21:321-326. © 2003 Wiley-Liss, Inc.