The vast majority of p53-regulated genes are induced in response to various stress signals and are responsible for maintaining genetic stability, DNA repair, regulation of crucial cell-cycle check points, and finally induction of apoptosis. The activity of p53 is tightly controlled by two major negative regulators including murine double minute 2 (MDM2; EC 6.3.2.19) and 4 (MDM4 or MDMX) proteins. Human MDM2 and MDMX are structurally related and contain three well-conserved domains: an N-terminal domain (responsible for p53 binding), a zinc-finger domain (function largely unknown) and a C-terminal RING domain (responsible for formation of homo- and heterodimers). Additionally, the RING domain of MDM2 confers E3 ubiquitin ligase activity. Concentration/activity of p53 is kept at low level in unstressed cells. This is accomplished by three parallel mechanisms mediated by MDM2 and/or MDMX. First, MDM2 and MDMX bind the N-terminal transactivation domain (TAD) of p53, preventing thereby its interaction with the transcription machinery and resulting in the inhibition of p53-responsive gene expression. Second, MDM2/X proteins export p53 outside the nucleus into the cytoplasm where it can no longer activate transcription. Finally, MDM2 marks p53 for proteasomal degradation[1]. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting the p53–MDM2 binding represents an attractive novel approach to cancer therapy[2].