MDM2 is an E3 ubiquitin ligase that regulates the activity of p53 by controlling degradation of the p53 protein, as a result of differential addition of ubiquitin. In the Advanced Online Publication of Nature Genetics, Parant et al. report the phenotype of mice lacking the recently cloned MDM2-related protein MDM4 (DOI:10.1038/ng714). They show that mdm4-null mice die at embryonic day 7.5-8.5. Analysis of the incorporation of the nucleotide analogue BrdU and TUNEL staining for apoptotic cells showed that, unlike mdm2-deficient embryos, death appears to be due to reduced cell proliferation and not induction of apoptosis. As with the mdm2-deficient lethality, loss of Trp53 rescued the lethal phenotype of mdm4-null embryos. Thus, in vivo the MDM2 and MDM4 proteins are non-overlapping regulators of p53 function.