Although allogeneic hematopoietic stem cell transplantation is an important therapy for many hematological and non-hematological diseases, acute graft-versus-host-disease (aGVHD) is a major obstacle to its success. The pathogenesis of aGVHD is divided into three distinct phases which occur largely as the result of interactions between infused donor T cells and numerous cell types of both hematopoietic and non-hematopoietic origin. In light of the disease's immensely complex biology, epigenetics has emerged as a framework with which to examine aGVHD. This review focuses on new findings that clarify the roles specific epigenetic regulators play in T cell-mediated aGVHD development and discusses how their modulation could disrupt that process to beneficial effects. DNA methyltransferases, histone methyltransferases and histone deacetylases are the most closely studied regulators across aGVHD priming, induction and effector phases and have been manipulated using drugs and other methods in both murine models and clinical trials to varying degrees of success. Antigen-presenting cells, effector T cells and memory T cells, among others, are targeted and affected by these regulators in different ways. Finally, our review highlights new directions for study and potential novel targets for modulation to abrogate aGVHD.