Improved patient tailored, more potent and durable treatment of childhood cancer is an urgent medical need. Childhood cancers are often still treated by a ‘one-fits-all’ approach, given the limited available entry points for targeted therapy. Molecular dissection of pediatric cancers, using multiple layers of information (so-called ‘omics’) up to the single cell level, is nowadays yielding fundamental insights into novel putative targets and strategies for precision oncology approaches. Importantly, childhood cancer differs in many aspects from adult cancers, the latter typically resulting from lifelong accumulation of genetic defects. In contrast, childhood cancers rather display a very low mutational burden and a unique biology of co-opted developmental pathways. Therefore, I aim to build a next-generation precision oncology platform for childhood cancer that will require a dedicated multidisciplinary and integrative scientific approach in which state-of-the-art technologies serve as driving forces to untangle the (epi)genetically rewired networks and fuel pre-clinical target evaluation.