SUMMARY/ABSTRACT Our proposed P01 entitled Discovering and Exploiting Mechanisms of Neuroblastoma (NB) Therapy Resistance is a multi-disciplinary and multi-institutional sustained assault on the unmet need of improving outcomes for children with the high-risk form of the disease. With the ambitious goals articulated in each Project to discover fundamental mechanisms of de novo and acquired therapy resistance to both standard and newly emerging therapies, the Program requires experienced leadership 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. With the guidance of a world-renowned scientific advisory board, Core A will 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.