Cells in our body are constantly exposed to various stresses and threats to their genomic integrity. The tumor suppressor protein p53 plays a critical role in successful defense against these threats by inducing apoptotic cell death or cell cycle arrest. In unstressed conditions, p53 levels and activity must be kept low to prevent lethal activation of apoptotic and senescence pathways. However, upon DNA damage or other stressors, p53 is released from its inhibitory state to induce an array of apoptosis and cell cycle genes. Conversely, inactivation of p53 could promote unrestrained tumor proliferation and failure to appropriately undergo apoptotic cell death, which could, in turn, lead to carcinogenesis. The ubiquitin E3 ligase MDM2 is the most critical inhibitor of p53 that determines the cellular response to various p53‐activating agents, including DNA damage. MDM2 activity is controlled by post‐translational modifications, especially phosphorylation. However, accumulating evidence suggests that MDM2 is also regulated at the level of protein stability, which is controlled by the ubiquitin‐proteasome pathway. Here, we discuss how MDM2 can be regulated in response to DNA damage with particular focus on the regulation of MDM2 protein stability. J. Cell. Physiol. 230: 2318–2327, 2015. © 2015 Wiley Periodicals, Inc.