The human body is actively protected against genetic damage by the activities of the major tumour suppressor p53. P53 responds dynamically to destructive stimuli, by promoting growth inhibition either permanently, or transiently to allow repair. Being a key cellular stress response protein, p53 levels and activities are kept under tight control. This critical regulation of p53 is executed by the Mdm proteins: Mdm2 and Mdmx, whereby Mdm2 regulates p53 stability and Mdmx controls its transcriptional activities. A mechanism selected in some cancers for breaking p53 tumour suppression is to elevate the Mdm proteins. We have identified in human breast cancer (BrCa) TMAs that levels of Mdmx are frequently elevated. Rationalizing that intervention to reduce Mdmx levels may restore p53 activities in breast cancer, we inducibly knocked down Mdmx in selected BrCa lines. In vitro growth of the BrCa lines was significantly inhibited by Mdmx knock down (KD). In an in vivo xenograft model of human BrCa, Mdmx KD was demonstrated to restrict tumour progression. These studies lay the foundation for a new approach to BrCa therapy with potential application across a range of sub-types.