The mouse/murine protein, MDM2, and its human homolog, HDM2, are important negative regulators of the p53 tumor suppressor protein. In normal, untransformed cells, MDM2 levels are tightly regulated to control expression of p53 and apoptosis. Conversely, MDM2 expression appears inherently higher in multiple types of cancer cells, thereby supporting its role as a suppressor of p53 pro-apoptotic activity. MDM2 amplification ranges between two- and ten-fold as reported in brain, breast, lung, and soft tissue tumors. MDM2 regulates p53 by two mechanisms: acting as a physical blockade of the transcriptional activation domain and E3 ubiquitin ligase. In addition to its relationship with p53, MDM2 behaves as an independent oncogene. These inherent characteristics make MDM2 a promising target for developing anti-cancer therapies. Investigators are now exploring both p53- dependent and independent cancer cell death pathways by targeting MDM2. Disrupting MDM2-p53 interaction with resultant increase in p53 induces cancer cell cycle arrest and apoptosis. Targeting over-expressed MDM2 on cancer cell membranes disrupts membrane integrity by pore formation, causing membrane destabilization and rapid cancer cell-specific necrosis. In this review, evidence supporting the evolving role of MDM2 as an anti-cancer target and a molecular-based tumor biomarker will be discussed.