Graft-versus-host disease (GVHD) is a significant cause of non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Existing strategies to prevent and treat GVHD are incomplete, where a significant portion of allo-HCT recipients developed this complication. Despite this, one such therapy has emerged involving the use of regulatory T cells (Tregs) to control GVHD. The use of natural Tregs (nTregs) yielded positive pre-clinical results and are actively under investigation to reduce GVHD. However, broad application of this approach may require standardization of Treg expansion methods and dosing. Inducible Tregs (iTregs) can be seamlessly generated, but controversial pre-clinical findings and phenotype instability have hampered their translation into the clinic. Here, we review the current biological differences between nTregs and iTregs, as well as their effects on GVHD and graft-versus-leukemia (GVL) responses. We conclude by exploring the idea of combinational cellular therapies for the prevention of GVHD and preservation of GVL.