Graft-versus-host disease (GvHD) in its acute and chronic forms continues to represent a significant barrier to the success and wide-applicability of blood and marrow transplantation as a potentially curative treatment modality for a number of benign and malignant blood conditions. Presently, calcineurin inhibitor (CNI)-based regimens remain the most commonly used prevention strategy, although post-transplant cyclophosphamide is emerging as an alternative approach, and is providing a backbone for innovative CNI-free combinations. In this paper, we review the current strategies used for the prevention of GvHD, and highlight some of the developing and promising combinations.