Despite prophylactic immune suppression, acute graft-versus-host disease (aGvHD) afflicts up to 45% of pediatric patients receiving allogeneic hematopoietic cell transplantation (alloHCT). AGvHD is responsible for nearly 20% of deaths following alloHCT and involvement of the gastrointestinal tract in the pathogenesis of aGvHD has been substantiated by the translation of pre-clinical and clinical studies. Emerging evidence suggests that perturbations in the microbiota diversity result in aberrant systemic immune response as well as pathogen colonization and mucosal invasion, fostering the development of GvHD. This presentation will provide a summary of the evidence on the microbiome and aGvHD and highlight a national trial investigating the efficacy of probiotic therapy for the prevention of aGvHD.