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, extensive inter- and intratumor heterogeneity has been demonstrated. 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 unknown. We put forward that a detailed characterization of the transcriptome of individual tumor cells, along with stromal and immune cells in a spatial context of tumor tissue may provide these insights.