Abstract Medulloblastoma (MB) is the most common pediatric CNS malignancy with varying prognoses depending on subgroup diagnosis. Group 3 MB displays the poorest overall prognosis, specifically in cases characterized by MYC hyperactivation. Current standard treatment can cause lifelong debilitating side effects, therefore the identification of targeted therapeutic agents will be critical in enhancing patient survival and bypassing therapy-induced aftereffects. We utilized the Pediatric Cancer Dependency Map to identify CDK8 as the most striking dependency in MB compared to all other pediatric malignancies. Further analysis revealed dependencies on its cognate cyclin, Cyclin C, and other members of the CDK8 kinase module (CKM). The CKM functions as a transcriptional regulator, phosphorylating RNAPol2 and other transcription factors. Interestingly, CDK8 dependency correlates with MYC amplification status in cell lines suggesting it to be a strong dependency in G3 MB. CDK8 expression, both RNA and protein, is highest in G3 tumors. We depleted CDK8 both genetically and pharmacologically and demonstrated downregulation of MYC expression in tumor cells and decreased cell survival. We next tested the efficacy of a CDK8 kinase inhibitor currently in clinical trials. Treatment with SEL-120 reduced cell proliferation and viability in vitro and inhibited tumor growth in vivo. This effect was limited to G3 models, as SEL120 showed little efficacy in SHH MB. Analysis of gene expression revealed that targeting CDK8 did not affect MYC-dependent gene expression but led to de-repression of differentiation genes regulated by PRC2. We further observed a global de-repression of H3K27me3 in cells treated with CDK8i. Finally, we tested the first ever blood-brain barrier penetrant CDK8i which mimics the activity of SEL-120 and potently synergizes with BETi, which antagonizes MYC signaling. In summary, we have identified and validated CDK8 as a novel target in G3 MB and identified a possible synergistic combination to move forward in clinical trials.