Neuroblastoma is a childhood tumor originating from cells of the developing sympathetic nervous system. The disease exhibits a remarkable phenotypic diversity reflected in the outcome, ranging from spontaneous regression to fatal disease. Mammalian achaete-scute homologue 1 (MASH-1 or HASH-1 in humans), a basic helix-loop-helix transcription (bHLH) factor, is transiently expressed in migrating sympatho-adrenal precursor cells. This gene, which is essential for proper development of the sympathetic nervous system, is expressed in a majority of primary neuroblastomas and neuroblastoma cell lines indicating an embryonal origin of the tumor. One important negative regulator of MASH-1 expression is the bHLH factor hairy and Enhancer of split homolog-1 (HES-1), which in turn is under positive control of the Notch signaling cascade. When neuroblastoma cells are induced to differentiate, as indicated by neuronal morphology and upregulation of neuronal marker genes, the HASH-1 expression is rapidly downregulated with a concomitant, transient upregulation of HES-1. Furthermore, a constitutively active form of Notch-1 inhibits induced differentiation of neuroblastoma cells. In this review, the role of the Notch-signaling cascade in neuroblastoma, with focus on the bHLH factors HASH-1 and HES-1, will be discussed.