Graft-versus-host disease (GVHD) limits the curative potential of allogeneic hematopoietic cell transplant (HCT). This immune-mediated disease can result in multisystem organ morbidity, chronic debility, or mortality. Prevention of GVHD is a primary objective when treating patients with allogeneic HCT. While many factors are considered in transplant planning, the choice of GVHD prophylaxis is a critical and modifiable factor that impacts the risk of GVHD. Each regimen is associated with variable GVHD risk, immune reconstitution, infection risk, graft-versus-tumor effect, and drug-related adverse events. Furthermore, the utility of a specific regimen must be considered in the context of the transplant platform such as conditioning regimen and donor choice. In this chapter, we review the current state of GVHD prophylaxis, highlighting the historical standard approach of calcineurin inhibitor-based regimens, as well as the emerging standard of post-transplant cyclophosphamide.