Neuroblastoma, a tumour of peripheral nerve, is the most common solid tumour of young children and in high-risk diseases, which comprises approximately half of patients, and the death from chemoresistant, metastatic relapse is very frequent. Children who relapse exhibit clonal enrichment of two genomic alterations: high-level amplification of the MYCN oncogene, and kinase domain mutations of the anaplastic lymphoma kinase (ALK) gene. Overall survival in this patient cohort is < 15% at 3 years, and there are few options for rationally targeted therapy. Neuroblastoma patients exhibit de novo resistance to existing ALK inhibitors, and no clinical therapeutics to target MYCN has yet been developed. This talk will outline our efforts to model aberrant expression of MYCN and ALK in neuroblastoma, and to uncover mechanisms of oncogenic action that are therapeutically targetable using small-molecule inhibitors. We describe a mechanistic interaction in which ALK upregulates MYCN transcription, and discuss clinical trials emerging from our work to develop transcriptional inhibitors of MYCN, and to identify effective inhibitors of ALK in neuroblastoma patients.