The neural crest is a multipotent transient cell population that migrates, proliferates, and differentiates in vertebrate embryogenesis and gives rises to a cornucopia of tissue derivatives such as craniofacial bone and cartilage, peripheral nerves, and glia. Congenital malformations including cleft palate and craniosynostosis arise from aberrant development of cranial neural crest cells and their derivatives. Neural crest derived tumors of Schwann cell lineages can arise from single genomic hits in the form of NF2 loss. Considering the low genomic burden of many neural crest derived tumors, we hypothesized that epigenetic regulators, which normally specify cell lineages and maintain cell fates in embryonic development, are mis-regulated in adult neural crest derived tissues, contributing to tumorigenesis and differential tumor radiation responses.Here we use mouse genetics and single cell sequencing to investigate how PRC2, a histone methyltransferase broadly involved in gene repression and maintenance of pluripotency in development, is involved in epigenetic control of post- otic neural crest derivates. We identified Eed, a PRC2 core subunit, as a potent regulator of craniofacial development. Eed deletion in post-migratory neural crest cells was perinatal lethal and knockout embryos presented with severe craniofacial abnormalities consistent with impaired differentiation of osteoblast derivatives. Using targeted primary cell culture gene expression analysis and unbiased scRNA-seq, we discovered changes in transcription factors involved in the proliferation and differentiation of neural crest derivatives including loss of Sox transcription factors and increase in Hox genes. Strikingly, we found an expansion of undifferentiated mesenchymal stem cells and decrease in differentiated osteoblast cells, indicating Eed controls proper differentiation of mesenchymal derivatives that comprise craniofacial structures. Taken together, we establish the embryonic, cellular, and molecular consequences of Eed loss in neural crest derived craniofacial tissues. Next, we investigated more broadly how epigenetic regulation contributes to cancer of neural crest derived cells including the tumorigenesis of schwannomas and schwannoma radiation responses. Using bulk and single-cell bioinformatics, functional genomic approaches, and mechanistic validation, we discovered schwannomas comprise 2 molecular subgroups marked by activation of neural crest signaling pathways or enrichment of immune cells in response to radiotherapy. CRISPRi radiation screening in human schwannoma cells identified the lysine demethylases KDM1A and KDM5C as drivers of radioresistance or radiosensitivity, respectively. Lastly, we integrated single-nuclei ATAC, RNA, and CRISPRi perturbation to identify chromatin accessibility motifs that drive schwannoma cell state evolution and radiation responses.