Neuroblastoma (NB), the most common extracranial solid tumor in children, is characterized by remarkable cellular heterogeneity and clinical variability ranging from spontaneous regression to aggressive progression and relapse. Despite advances in multimodal therapies, including surgery, chemotherapy, radiotherapy, differentiation therapy, and immunotherapy-treatment resistance remains the principal barrier to improving survival in high-risk patients. Recent single-cell and spatial multi-omics studies have revolutionized our understanding of NB by revealing its developmental origins, lineage hierarchy, and adaptive evolution under therapeutic pressure. These technologies have delineated distinct cellular states along an adrenergic-mesenchymal continuum and uncovered the dynamic interplay between tumor cells and their microenvironment. Genetic instability, epigenetic reprogramming, and metabolic plasticity cooperate with immune and stromal remodeling to drive tumor persistence and relapse. At the molecular level, mechanisms such as MYCN-driven chromatin remodeling, super-enhancer reorganization, bypass signaling activation, quiescent persister programs, immune checkpoint engagement, and metabolic rewiring collectively enable therapeutic escape. Importantly, these processes are reversible, highlighting tumor plasticity as both a hallmark and a potential vulnerability of NB. Integrating single-cell transcriptomics, epigenomics, and spatial profiling provides an unprecedented framework to map resistance evolution, identify lineage-specific vulnerabilities, and guide rational combination strategies. Targeting epigenetic regulators, metabolic checkpoints, and immune suppressive networks in a temporally coordinated manner holds promise for converting NB from an adaptive to a controllable disease.© 2025. The Author(s).