The genomics revolution has revealed remarkably simple genomes as a defining feature of many pediatric cancers. These cancers are often driven by key initiating events involving aberrant transcription factors or abnormalities of an epigenetic regulator. For example, MYCN amplification in neuroblastoma is a well described recurrent abnormality and poor prognostic marker, EWS/ETS rearrangements are a defining feature of the pediatric solid tumor Ewing sarcoma, MLL-rearrangements are commonly found in infant leukemia, and mutations in histone H3.3 have been recognized as initiating events in pediatric glioblastomas. We are taking a collaborative, integrated genomics approach to identifying new dependencies in pediatric cancers through the application of functional and chemical genomic approaches. Specifically, genomically characterized pediatric cancer cell lines are screened using genome-wide shRNA and CRISPR/Cas9 and bioactive chemical libraries to connect disease lineage or genotype with response to either gene suppression/knockout or small-molecule inhibition. High-risk pediatric cancers, including neuroblatoma, were nominated as top priority diseases for screening. Emerging targets scoring in this screening effort in MYCN-amplified neuroblastoma will be presented.