Steroid-resistant or refractory acute GVHD (SR-aGVHD) poses one of the most vexing challenges faced by providers who care for patients after allogeneic hematopoietic cell transplantation. For the past 4 decades, research in the field been driven by the premise that persistent GVHD results from inadequate immunosuppression. Accordingly, most efforts to solve this problem have relied on retrospective or prospective studies testing agents that have direct or indirect immunosuppressive effects. Retrospective studies far outnumber prospective studies, and no controlled prospective trial has shown superior results for any agent over others. Truth be told, we do not know how to treat SR-aGVHD. Preclinical work during the past decade has provided fresh insights into the pathogenesis of acute GVHD, and translation of these insights toward development of more effective treatments for patients with SR-aGVHD has at last begun. Given the limited state of current knowledge, this "How I Treat" review highlights the overriding imperative to avoid harm in caring for patients with SR-aGVHD. Prospective trials that are widely available are urgently needed to advance the field.