Our research centers on the idea that two of the most deadly nervous system cancers—glioblastoma and high‐risk neuroblastoma—exploit the very developmental programs that normally guide neural crest cells and brain vasculature, turning them to malignant ends. In essence, we’ve discovered that re‑awakening these embryonic trajectories fuels tumor diversity and aggressiveness, yet the precise cellular states responsible remain poorly understood. To address this gap, we map the “developmental states” within patient‑derived tumors, revealing, for example, that neuroblastomas harbor cell populations with broad epigenetic priming and dynamic cross‑talk with their microenvironment, while a subset of glioblastomas recapitulates a neural crest–perivascular lineage. We interrogate these phenomena using cutting‑edge single‑cell and spatial Multi‑Omics to resolve cellular hierarchies in situ, deep‑learning analytics (our scCAMEL platform) to integrate high‑dimensional data and predict lineage transitions, and both human organoid systems and genetically engineered animal models to validate our findings in vivo. Ultimately, by pinpointing the molecular switches that drive developmental plasticity in these tumors, we aim to expose vulnerabilities that can be targeted therapeutically, disrupting the very pathways that underlie tumor heterogeneity and improving outcomes for patients facing these formidable cancers.