Graft-versus-host disease (GvHD) is the major cause of transplant-related mortality and morbidity. As it is closely related to the major therapeutic principle, graft-versus-leukaemia (GvL) effect, risk assessment has to balance both risks depending on the pre-transplant status. This is clearly demonstrated when comparing the two major strategies for prevention of GvHD. While the majority of approaches aiming at T-cell depletion show efficacy in reducing acute and chronic GvHD and transplant-related mortality, T-cell depletion also affects graft-versus-leukaemia effects and thus results in a higher relapse rate. Thus, standard prophylaxis relying on calcineurin inhibitors frequently results in at least equivalent or even superior long-term disease-free survival, and the risk of relapse has to be considered when selecting regimens for prevention of GvHD. In addition to this general dilemma, drug-specific side-effects and risks have to be considered when selecting regimens for GvHD prevention and treatment.