Allogeneic hematopoietic stem cell transplantation (allo-SCT) offers cure for a variety of conditions, in particular but not limited to hematologic malignancies. However, it can be associated with life-threatening complications, including graft-versus-host disease (GVHD) and infections, that are factors limiting its widespread use. Technical advances in the field of microbiome research have allowed for a better understanding of the microbial flora of the human intestine and dissection of their interactions with the host immune system in allo-SCT and post-transplant complications. There is growing evidence that the commensal microbiome is frequently dysregulated following allo-SCT, and that this dysbiosis can predispose to adverse clinical outcomes, especially including acute intestinal GVHD as well as reduced overall survival. In this review, we discuss the interactions between the microbiome and the components of the immune system which play a major role in the pathways leading to the inflammatory state of acute intestinal GVHD. We also discuss the microbiome-centered strategies that have been devised or are actively being investigated in order to improve the outcomes of allo-SCT patients with regards to acute intestinal GVHD.