Over the past 50 years there has been a dramatic improvement in cure rates for childhood cancers, with overall survival now reaching 75%. This astounding success has been achieved through the judicious use of cytotoxic agents, however the therapeutic ceiling has been reached utilising these conventional chemotherapies and radiotherapy. This presentation will focus on our program of translational research for the development and clinical testing of novel therapies for the most aggressive childhood cancers. Brain tumours are now the disease entity responsible for the highest number of deaths in childhood and high-grade gliomas (HGG), including diffuse intrinsic pontine gliomas (DIPG) remain completely incurable from diagnosis. We have oped a national DIPG autopsy study, and developed a bank of tumours and DIPG cultures that has facilitated new discoveries in DIPG biology and therapeutics. Leading drug candidates targeting the epigenome, metabolic pathways, the cell cycle apparatus and immune responses are currently being tested for translation into early phase clinical trials for children with this incurable disease. The development of precision medicine approaches are another strategy to improving the outcomes for brain tumour and other high risk paediatric cancer patients. The Zero Childhood Cancer precision medicine program is a national platform for children with high risk malignancies, combining whole genome sequencing, RNA sequencing, high throughput drug screening, and personalised orthotopic mouse models, with the aim of identifying individualised treatments. The results of the pilot TARGET trial will be presented, as well as the preliminary results of the ongoing national PRISM trial. This trial opened in 2017 at every paediatric oncology centre in Australia, and as of December 2018 had enrolled over 170 high risk paediatric cancers. Two thirds of patients have had treatment recommendations and the impact of these findings on patient management and outcome will be presented.