Background: The overall survival rate for children with solid tumors has plateaued over the past 2 decades and survival rates remain at or below 30% for children with recurrent or metastatic disease. This plateau comes at a time when pediatric oncologists have access to an unprecedented diversity and number of new oncology drugs. In addition to these advances in drug development, it is now feasible to obtain complete genomic profiling of each patient’s tumor using Next Generation Sequencing (NGS). Several clinical genomic efforts have been launched including the Pediatric MATCH trial that seeks to evaluate molecularly targeted therapies in children with advanced cancers. As the concept of a “druggable” mutation is one that is still being refined in pediatric solid tumors, this study seeks to use a diverse collection of orthotopic murine patient derived xenografts (PDXs) generated through the Childhood Solid Tumor Network (CSTN) to study these potentially actionable mutations in the preclinical setting. Methods: Over 60 PDX models representing the major pediatric solid malignancies in the CSTN were analyzed using histology, electron microscopy, gene expression profiling, whole genome sequencing, exome sequencing, RNA-seq and DNA methylation. Pharmacokinetic studies of the drugs being used in the Pediatric MATCH trial were performed in tumor bearing mice to determine matched human AUC-guided dosing. Preclinical studies were performed using PDX models with identified druggable mutations according to the Pediatric MATCH study as well as those lacking the mutation for control. Results: Several druggable mutations were identified in the genomic analysis of the PDX tumors including ALK, ROS1, TSC1, FGFR4, MAPK, SMARCB1, ATM, and NTRK1. Mouse equivalent dosing was successfully obtained through PK studies for all of the drugs that match the found mutations. Preclinical efficacy studies using the PDX tumors with and without identified druggable mutations are currently underway. Results of these studies will be presented at the annual meeting. Conclusions: The testing of molecularly targeted therapeutics in PDX models of pediatric solid tumors is feasible and may be beneficial to understanding the driver mutations and underlying biology of these malignancies. We hope to continue to use these PDX models created through the CSTN to help prioritize agents for further clinical trial development for pediatric patients.