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The purpose of this work is to provide the research community with a robust functional screening approach for identification of novel oncogenic drivers of neuroblastoma as a starting point for the development of new therapies. Furthermore to use this technology to start identifying novel oncogenic drivers ourselves. To do this we have established a novel system to functionally screen candidate oncogenic drivers through the transformation of primary neural crest cells into neuroblastoma. Through work supported by this grant we have evidence that ARID1A is an important tumor suppressor that can collaborate with N-Myc in initiating neuroblastoma through our transformation of primary mouse neural crest cells into phenotypically accurate neuroblastoma. We have also advanced our screening technology by an over 300- fold improvement in the number of primary neural crest cells generated per isolated neural tube, which will allow us to screen highly complex pools of candidate neuroblastoma oncogenic drivers. We have also made significant advances in establishing complementary in vitro screening approaches that can validate positive hits from our tumor screen and that can identify oncogenic drivers that may be missed by our more stringent in vivo tumor assay.