Since the discovery of Mdm2, the contribution of this RING E3 ubiquitin ligase to the pathobiology of cancer has focused almost exclusively on its role as a negative regulator of the p53 tumor suppressor. Under normal conditions, Mdm2 promotes the ubiquitin- and proteasome-dependent degradation of p53. Levels of p53 are thus kept sufficiently low to allow for cell survival and cell cycle progression. In the context of such insults as DNA damage or ribosomal stress, however, the Mdm2-p53 interaction is disrupted and p53 is stabilized. The myriad intracellular outcomes of p53 activation together comprise a robust program of tumor suppression that is short-circuited in cancer. Over half of all human malignancies are known to have lost p53 expression or sustained p53 mutation, whereas many of the remaining tumors harbor other alterations in key mediators of p53 activity that include overexpression of Mdm2. Therapies targeting the interaction between Mdm2 and p53 represent a possible means of pharmacologically reactivating the p53 pathway in this latter setting. The degree of overlap across the biological consequences of either p53 loss or Mdm2 overexpression, however, has not been thoroughly explored. Indeed, a body of evidence for several p53-independent functions of Mdm2 suggests that disrupting the Mdm2-p53 interaction may fail to address the full spectrum of oncogenic effects specific to tumors that overexpress Mdm2.