Neuroblastoma is one of the most frequent solid tumors in children and is responsible for 15% of all childhood cancer deaths. Over the last 2 decades, several bulk (i.e. whole tumor tissue) -omics technologies have resulted in important insights into inter-tumor heterogeneity, ultimately resulting in more refined risk groups and novel targeted therapies (e.g. ALK inhibition). Nevertheless, despite intensive and multimodal risk-adapted therapies, approximately half of children with high-risk neuroblastoma relapse and ultimately die from their disease. To leap forward, we need better insights into resistance and relapse mechanisms. We have clues that acquired DNA mutations (e.g. TP53), upregulation of cellular efflux pumps, cell-state plasticity, (de)differentiation, cancer stem cells, hypoxia, immune cell infiltration and depletion, amongst others, play a role in resistance, but their interdependence and spatial organization are largely unknow. We put forward that a detailed characterization of the transcriptome and the genome of individual tumor cells, along with stromal and immune cells in a spatial context of the tumor tissue may help provide these insights.