THE gene p53 encodes a transcriptional activator(1,2) of genes involved in growth arrest(3,4), DNA repair(5) and apoptosis(6-8). Loss p53 function contributes to tumor development in vivo(9-11). The transcriptional activation function of p53 is inactivated by interaction with the mdm2 gene product(11-14). Amplification of mdm2 has been observed in 36% of human sarcomas, indicating that it may represent an alternative mechanism of preventing p53 function in tumor development(15). To study mdm2 function in vivo, we generated an mdm2 null allele by homologous recombination. Mdm2 null mice are not viable, and further analysis revealed embryonic lethality around implantation. To examine the importance of the interaction of MDM2 with p53 in vivo, we crossed mice heterozygous for mdm2 null alleles. Rescue of the mdm2(-/-) lethality in a p53 null background suggests that a critical in vivo function of MDM2 is the negative regulation of p53 activity.