Summary Acute graft‐versus‐host disease (GVHD) is a leading cause of non‐relapse mortality following allogeneic haematopoietic cell transplantation. Attempts to improve treatment response in clinically‐established GVHD have not improved overall survival, often due to the increased risk of infectious complications. Alternative approaches to decrease GVHD‐related morbidity and mortality have focused on the ability to predict GVHD prior to clinical manifestation in an effort to provide an opportunity to abort GVHD development, and to gain new insights into GVHD pathophysiology. This review outlines the research efforts to date that have identified clinical and laboratory‐based factors that are predictive of acute GVHD and describes future directions in developing algorithms that will improve the ability to predict the development of clinically relevant GVHD.