Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Despite major advances in the understanding of GVHD pathogenesis, standard GVHD prophylaxis regimens continue to be based on the combination of a calcineurin inhibitor with an antimetabolite, while first line treatments still rely on high-dose corticosteroids. Further, no second line treatment has emerged thus far in acute or chronic GVHD patients who failed to respond with corticosteroid treatment. After briefly reviewing current standards of GVHD prevention and treatment, this article will discuss recent approaches that might change GVHD prophylaxis/treatment for decades to come, with a special focus on recently developed immunoregulatory strategies based on infusion of mesenchymal stromal or regulatory T-cells, or injection of low-dose interleukin-2.