Novel pharmacological strategies capable of inhibiting pro-oncogenic MDM2 beyond its p53-dependent functions represent increasingly attractive therapeutic strategies to treat solid and hematological cancers that are dependent upon MDM2/MDMX, regardless of mutational status. Utilizing a novel first-in-class cell-penetrating peptide disruptor of MDM2 homo- and heterodimerization (DRx-098D), we demonstrate the anti-proliferative potential of blocking MDM2 dimerization against a panel of human cancer cell lines that are wild type, mutant, or null. DRx-098D elicits its anti-cancer activity via a differentiated mechanism vs. idasanutlin (a phase 3 clinical candidate MDM2-p53 small-molecule inhibitor), inducing significantly superior growth inhibition against null HCT116 cells. Our preliminary data highlight, for the first time, the potential therapeutic utility of exploiting both MDM2 homo- and heterodimerization in wild-type and mutant cancers with an MDM2-derived disruptor peptide.