Graft-versus-host disease (GVHD) represents the most serious and challenging complication of allogeneic haematopoietic stem-cell transplantation (HSCT). New insights on the role of regulatory T-cells, T cells, and antigen-presenting cells have led to an improved understanding of the pathophysiology of GVHD. However, little progress has been made since the introduction of calcineurin-inhibitor-based regimens in the mid-1980s. Despite standard prophylaxis with these regimens, GVHD still develops in approximately 40–60% of recipients. Thus, there is a need for developing newer approaches to mitigate GVHD, which may facilitate the use of allogeneic HSCT for the treatment of a wider range of haematological cancers. We discuss the rationale, clinical evidence, and outcomes of current (and widely employed) strategies for GVHD prophylaxis, namely calcineurin-inhibitor-based regimens (such as cyclosporine or tacrolimus) combined with methotrexate or mycophenolate mofetil. We assess the clinical evidence for emerging approaches in the prevention of GVHD, including therapies targeting T cells or B cells, the use of mesenchymal stem cells, chemo-cytokine antagonists (such as maraviroc, TNF-α inhibitor, IL-2 receptor antagonist, IL-6 inhibitor), and the use of novel molecular regulators that target multiple cell types simultaneously, including atorvastatin, bortezomib, and epigenetic modulators.