The optimum graft-versus-host disease (GVHD) management in today's clinical practice remains controversial. There is an enormous heterogeneity among transplanters in their therapeutic decisions for each individual patient with GVHD. Existing guidelines do not always cover many unique clinical scenarios. Consequently, a significant number of allograft recipients fail either because of severe GVHD or relapse of underlying malignancy. Until more effective methods are available, tailoring the current GVHD management by modification of immunosuppressive therapy in each patient based on disease and transplant characteristics may decrease the mortality. The purpose of this review is to raise several questions among readers about GVHD management and generate new hypotheses, which may need to be tested in cooperative group studies.