In this review, we discuss the role of these pathways in the therapy-resistant phenotype of p53-null and/or MYCN-amplified NB, the signaling mechanisms that mediate the aggressive and treatment-resistant behavior of refractory NB, the mechanisms of action of didymin, and key in vivo data in animal models that can facilitate the clinical translation of didymin in the treatment of NB. This evidence concerns the gene TP53 and neuroblastoma.