Cholestatic liver diseases are among the most important liver disorders that occur in infants and children, leading to devastating morbidity and accounting for over 70% of liver transplants performed during childhood, thus posing a major public health burden. Although major advances in genetics of these disorders have been made over the past decade, therapeutic options are limited. Investigation of these disorders promises to advance scientific knowledge about hepatobiliary development, hepatocyte transporters, cholangiocyte biology, genetic regulatory networks, the neonatal immune response and mechanisms of injury, as well as the discovery of biomarkers of disease and testing of new diagnostic and therapeutic strategies. With the advent of next generation sequencing, genomics/epigenomics, proteomics and metabolomics, disease modeling paradigms and a pipeline of new potential therapies, the immediate translational impact of research in these disorders has never been greater. The 8 cholestatic disorders of the Childhood Liver Disease Research Network (ChiLDReN) have been studied in multi-centered research consortia at our Center for the past 22 years, during the last 15 years within ChiLDReN. Members of our Clinical Center at the University of Colorado Denver and Children’s Hospital Colorado have played major leadership roles as the Chair of the Steering and Executive Committees of ChiLDReN and Chairs of 4 protocols, among other roles. The objectives of this grant application in response to NIH RFA-DK-23-017 through our four specific aims are: to be chosen to be an active, collaborative and productive Clinical Center in the next version of ChiLDReN; to continue to enroll participants with biliary atresia and primary sclerosing cholangitis in the respective protocols and to continue to follow those already enrolled in all of the ChiLDReN ongoing protocols; complete, analyze and publish all of the ChiLDReN study protocols; to be an active participant in all new investigations, protocols and clinical trials initiated by the Network; to develop and propose new clinical and translational studies, trials and ancillary studies that will utilize our participant populations and existing data and biospecimens; to maintain leadership roles within the network and direct the Administrative Core Functions of ChiLDReN; to subcontract to Children’s Hospital Los Angeles for their ongoing work within the ChiLDReN Network; and to continue to provide PFIC/BRIC/ALGS Genotyping expertise and services. Through these activities, our Colorado ChiLDReN Clinical Center will enhance and build on the ChiLDReN goals of expanding clinical and translational research on 8 rare pediatric liver diseases focusing upon improving our understanding of these disorders and developing novel diagnostic and therapeutic strategies.