We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection. Display omitted •Proteogenomics characterization of 218 pediatric brain tumor samples of 7 histologies•Proteomic clusters reveal actionable biological features spanning histological boundaries•Proteomics reveal downstream effects of DNA alterations not evident in transcriptomics•Kinase activity analyses provide insights into pathway activities and druggable targets Integrative proteogenomics analysis of pediatric tumors identifies common underlying biological processes and potential treatments as well as the functional effects of somatic mutations and CNVs driving tumorigenesis.