Human neural stem cell cultures provide experimental access to progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. We evaluated human neuroepithelial stem (NES) cells, representative of cerebellar progenitors for ability to generate medulloblastoma, the most common malignant brain tumor. Since amplification of MYCN in medulloblastoma is associated with poor prognosis, we transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from these xenograft tumors were globally more representative of human medulloblastoma subtypes than a MYCN-driven genetically engineered mouse model. Similarly, NES cells generated from patients with Gorlin syndrome, a tumor predisposition syndrome harboring germline mutated PTCH1, also produce medulloblastoma. We then mutated candidate cooperating genes in Gorlin NES cells and found that mutation of DDX3X or loss of GSE1 accelerated tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.