The MYCN oncogene plays an important role in the pathogenesis of neuroblastoma. It is amplified in more than 30% of high-risk cases and over expression induces neuroblastoma in transgenic mice. MYCN amplification/overexpression is found in many types of cancers including neuroblastoma, medulloblastoma and other aggressive tumors of neuroectodermal origin as well as in rhadomyosarcoma and small cell lung cancers. MYCN exerts its oncogenic effects through transcriptional regulation of numerous target genes. We have recently characterized the p53 inhibitor MDM2 (HDM2) as one such target in MYCN amplified neuroblastoma cell lines. Conditional expression of MYCN yields elevated MDM2 mRNA and protein. MYCN inhibition leads to diminished MDM2, stabilized p53 and apoptosis. As the primary negative regulator of p53, MDM2 is critically regulated in normal cells to ensure adequate p53 activity in response to damage or stress. Additionally, MDM2 regulates many p53 independent processes pertinent to oncogenesis. We propose that increased MDM2 levels downstream of MYCN are tumorigenic secondary to disruption of multiple p53 dependent and independent mechanisms controlling genomic stability, apoptopsis and cell cycle progression. Further research into the MYCN/MDM2 regulated pathways will provide insight into the pathogenesis of MYCN-driven tumors and provide targets for novel therapeutic interventions.