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The MYC family oncogenes cause transformation and tumor progression by corrupting multiple cellular pathways, altering cell cycle progression, apoptosis, and genomic instability. Several recent studies show that MYCC (c-Myc) expression alters DNA repair mechanisms, cell cycle checkpoints, and karyotypic stability, and this is likely partially due to alterations in centrosome replication control. In neuroblastoma cell lines, MYCN (N-Myc) expression induces centrosome amplification in response to ionizing radiation. Centrosomes are cytoplasmic domains that critically regulate cytokinesis, and aberrations in their number or structure are linked to mitotic defects and karyotypic instability. Whereas centrosome replication is linked to p53 and Rb/E2F-mediated cell cycle progression, the mechanisms downstream of MYCN that generate centrosome amplification are incompletely characterized. We hypothesized that MDM2, a direct transcriptional target of MYCN with central inhibitory effects on p53, plays a role in MYC-mediated genomic instability by altering p53 responses to DNA damage, facilitating centrosome amplification. Herein we show that MYCN mediates centrosome amplification in a p53-dependent manner. Accordingly, inhibition of the p53-MDM2 interaction with Nutlin 3A (which activates p53) completely ablates the MYCN-dependent contribution to centrosome amplification after ionizing radiation. We further show that modulating MDM2 expression levels by overexpression or RNA interference-mediated posttranscriptional inhibition dramatically affects centrosome amplification in MYCN-induced cells, indicating that MDM2 is a necessary and sufficient mediator of MYCN-mediated centrosome amplification. Finally, we show a significant correlation between centrosome amplification and MYCN amplification in primary neuroblastoma tumors. These data support the hypothesis that elevated MDM2 levels contribute to MYCN-induced genomic instability through altered regulation of centrosome replication in neuroblastoma.