Acute graft-versus-host disease (GVHD) is 1 of the major life-threating complications after allogeneic cell transplantation. Although steroids remain first-line treatment, roughly one-half of patients will develop steroid-refractory GVHD (SR-GVHD), which portends an extremely poor prognosis. Many agents that have shown encouraging response rates in early phase 1/2 trials for prevention and treatment have been unsuccessful in demonstrating a survival advantage when applied in the setting of SR-GVHD. The discovery of novel treatments has been further complicated by the absence of clinically informative animal models that address what may reflect a distinct pathophysiology. Nonetheless, the combined knowledge of established bone marrow transplantation models and recent human trials in SR-GVHD patients are beginning to illuminate novel mechanisms for inhibiting T-cell signaling and promoting tissue tolerance that provide an increased understanding of the underlying biology of SR-GVHD. Here, we discuss recent findings of newly appreciated cellular and molecular mechanisms and provide novel translational opportunities for advancing the effectiveness of treatment in SR-GVHD.