Abstract Despite intense efforts, the cure rates of childhood leukemias and solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. In this presentation, I will describe my laboratory’s recent efforts to apply functional proteomic and genomic technologies to identify causal mechanisms of childhood cancer pathogenesis and therapy resistance. I will present functional proteomic studies of pediatric acute myeloid leukemias, identifying kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML. I will also present studies of site-specific genomic rearrangements in childhood solid tumors, identifying the PGBD5 DNA transposase as their oncogenic mutator. Lastly, I will present synthetic lethal approaches to leverage functional dependencies of transcription factor control and PGBD5-dependent DNA damage signaling to induce specific antitumor effects while sparing normal cells, including therapeutic strategies suitable for immediate translation to clinical trials. Citation Format: Alex Kentsis. Functional proteomics and site-specific genomic rearrangements of pediatric cancers [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA25.