Neuroblastoma is a pediatric tumor that originates from precursor cells of the sympathetic nervous system that have discontinued their normal differentiation program. This review is focused on involvement of the Notch signaling cascade in the process of differentiation in neuroblastoma cells and normal cells of the sympathetic nervous system. Hypoxia induces dedifferentiation of neuroblastoma cells in vivo and in vitro, and under oxygen-compromised conditions the Notch cascade is activated. This activation might promote development of the dedifferentiated phenotype. The implications of these observations for tumor biology are also discussed.