Mdm2 and MdmX are two closely related proteins that have been well-characterized as negative regulators of the tumor suppressor p53. Their interplay and especially respective roles in ubiquitination and subsequent degradation of p53 have lacked clarity. Yang and colleagues now demonstrate an obligate role for MdmX in recruitment of the E2 ubiquitin ligase UbcH5c to the Mdm2-MdmX hetero-oligomer. The use of elegant genetically engineered mouse models ensures the biological relevance of their findings that have important implications for targeted therapies involving these key players in the p53 pathway.See related article by Yang et al., Cancer Res 2021;81:898-909.