Abstract The cellular stress response pathway regulated by the p53 tumor suppressor is critical to the maintenance of genomic integrity and to the prevention of oncogenic transformation. Intracellular levels of p53 are tightly regulated by an autoregulatory feedback loop comprised of p53 and MDM2. It might be predicted that disruption of this loop, either through p53 mutation or overexpression of MDM2, would be a negative prognostic marker for cancer development, likelihood of relapse, or response to therapy. In fact, although MDM2 overexpression is common in cancer, it can be both a positive and a negative predictor of outcome in different tumors, and its significance as a biomarker remains controversial. Data from a number of different tumor types are reviewed for the predictive significance of MDM2 expression, along with evidence for different mechanisms of MDM2 overexpression in these different tumors. In light of the biological complexities underlying the p53-MDM2 loop, it is, perhaps, not surprising that no simple paradigm exists that is generally applicable. Much work remains to be done to elucidate the basic mechanisms underlying the physical interactions between the two proteins, the role of protein modifications in altering those interactions, and also the genetic and transcriptional deregulations by which protein levels are altered in human cancers. Only in this way will truly biologically relevant predictive factors emerge.