Pediatric tumors such as neuroblastoma are characterized by a genome-wide ‘transcrip-tional burden’ surmising the involvement of multiple alterations of gene expression. Search for master regulators of transcription whose inactivation is lethal for tumor cells identified the non-POU domain-containing octamer-binding protein (NONO), a member of the Drosophila Behavior/Human Splicing family known for the ability to form com-plexes with macromolecules. NONO emerges as an essential mechanism in normal neu-rogenesis as well as in tumor biology. In particular, NONO interactions with RNAs, largely with long non-coding MYCN transcripts, have been attributed to the aggressive-ness of neuroblastoma. Broadening its significance beyond MYCN regulation, NONO guards a subset of transcription factors that comprise a core regulatory circuit, a self-sustained loop that maintains transcription. Furthermore, as a component of pro-tein-protein complexes, NONO has been implicated in the control of cell cycle progres-sion, double strand DNA repair and, generally, cell survival. Altogether, the pro-oncogenic roles of NONO justify the need for its inactivation as a therapeutic strategy. However, con-sidering NONO as a therapeutic target, its druggability is a challenge. Recent advances in inactivation of NONO and downstream signaling with small molecular weight com-pounds make promising the development of pharmacological antagonists of NONO pathway(s) for neuroblastoma treatment.