p53 missense mutations observed in human cancers are often associated with an increased level of p53 protein in the tumour. Using mouse models, Terzian et al. recently showed that this accumulation of mutant p53 protein is not associated with specific properties of the protein itself but instead depends on the endogenous genetic background of the tumours and on two important genes, mouse double minute 2 (Mdm2) and the cyclin kinase inhibitor p16INK4a. Mice expressing mutant p53 in the absence of Mdm2 display more aggressive metastatic tumours. In light of these observations, targeting the MDM2-p53 interaction for therapy of human cancer could be more complicated than previously anticipated.