The Zero Childhood Cancer (ZERO) program provides a comprehensive precision medicine approach to High-Risk paediatric malignancies (less than 30% survival) to improve treatment outcomes. We developed a pipeline to increase the utility of transcriptome sequencing (RNA-seq) in precision medicine to identify driver fusions, somatic mutations from RNA and over-/under-expressed genes. Through deeper exploration of RNA-seq beyond expression analysis and integration with whole genome sequencing, the RNA-seq pipeline has expanded the targeted therapeutic options to 72% of patients and a driver mutation identified in 94%. Here we will present our bioinformatic approaches to integrating the pipelines and the additional clinical utility a comprehensive RNA-seq pipeline provides and its impact on patient management and response.