Paediatric precision oncology platforms (INFORM, MAPPYACTS, iTHER) have prospectively analyzed over 1.000 relapsed paediatric cancers by next generation sequencing (WGS, WES, RNAseq) and microarray-based technologies (methylome, transcriptome). While targets can be identified in 50% of cases, the remaining patients lack actionable alterations. This occurs particularly in brain tumors, sarcomas and neuroblastoma, indicating significant, currently unmet needs in precision medicine. Here, we propose that direct functional drug response profiling of patient-derived cancer cells (PDCs) will provide additional key information for precision paediatric oncology. The COMPASS consortium has four main aims: I) establish a standardized ex vivo drug response profiling platform to discover unexpected drug efficacies and drug re-positioning opportunities, II) discover new biomarkers and molecular mechanisms for the drug efficacies seen, III) generate a large-scale online data resource of drug efficacies with integrated omics data providing a basis for novel precision therapies for incurable paediatric tumors and IV) clinical translation. To achieve a high concordance in a multi-center setting, we will share SOPs, a core set of genetically defined paediatric PD tumor models and a COMPASS core library containing clinically approved drugs. We believe that this consortium will deliver breakthrough insights based on the following strengths i) integration of samples, knowhow as well as clinical and molecular data from key European centers in paediatric oncology, ii) significant track record in collecting multi-omics data from 1000+ paediatric oncology cases, iii) incorporation of direct functional high-content 3D drug response profiling of PDs as a new platform for efficacies of cancer drugs for individual patients and iv) creating an open-access data resource of molecular and functional profiles for facilitating clinical trials and future precision clinical cancer care.