Despite rapid increase in the utilization of allogeneic hematopoietic stem cell transplantation, non-relapse mortality and sequela from acute graft-versus-host disease (GVHD) remain principle barriers. GVHD involves complex interactions between innate and adaptive immunity, culminating in tissue damage by inflammatory mediators and cellular effectors. Recently, our understanding of the molecular intricacies of GVHD has grown tremendously. New insights into the roles played by novel cytokines, chemokines, intracellular signaling pathways, epigenetics and post-translational modifications of proteins in GVHD biology provide numerous targets that might be therapeutically exploited. This review highlights recent advances and identifies opportunities for reshaping contemporary GVHD therapeutics.