CORE A SUMMARY/ABSTRACT This revised competing renewal Program Project Grant application entitled Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance is a multi-disciplinary and multi-institutional translational research Program focused on the unmet need of improving outcomes for children with high-risk neuroblastoma. We report significant progress towards our original scientific and clinical trial goals and report herein our ambitious new research strategies as articulated in each Project and Core B. Together, we seek to discover fundamental mechanisms of de novo and acquired resistance to both standard and newly emerging therapies. Core A provides the experienced leadership and administrative infrastructure to define priorities, sustain momentum, and deliver results that meet defined milestones. Thus, Core A will provide the scientific, budgetary, and administrative leadership, as well as the programmatic infrastructure, to achieve the translational mission of the proposed investigation across all eight leading childhood cancer research institutions. Unique to our Program is the New Approaches to Neuroblastoma Therapy (NANT) clinical trials consortium (eleven full member sites, six guest member sites, and expanding European membership) embedded in Core B, along with biorepository, pathology, flow cores, and statistical expertise, to enable rapid translation of Project discoveries to our patients. With the guidance of a world-renowned Scientific Advisory Board, Core A will continue to oversee the development of a new generation of rationally designed therapies for children with NB that we expect to ultimately improve cure rates, while simultaneously reducing both short- and long-term toxicities.