While the role of donor-specific antibodies in solid organ transplantation is well established, their importance in hematopoietic stem cell transplantation is only now becoming clear. A review of the literature reporting on HLA immunization in hematopoietic stem cell transplantation provides ample circumstantial evidence that donor-specific antibodies are associated with a twofold to tenfold increase of graft failure of HLA-mismatched hematopoietic stem cell transplantation, irrespective the type of the graft or the patient conditioning. Hematopoietic stem cell transplantation with HLA-mismatched donors is for many patients the only curative option. Relapse of malignancy, graft versus host disease and post-transplant infection still poses considerable hurdles for transplant success. The contribution HLA antibodies to transplant outcome have been a relatively neglected focus until recently. However, not all HLA antibodies can cause graft failure which may depend on antigens involved, titre or other, as yet unravelled, functional antibody potentials. A higher number of stem cells may overcome rejection in the case of low strength antibodies, but it is impossible to give more specific recommendations. Even less can be concluded from approaches to reduce donor-specific antibodies. It seems reasonable to aim for a negative or low titre donor-specific antibodies at the moment of hematopoietic stem cell administration and to inhibit antibody-mediated cell destruction machinery by blocking the macrophage. Although the role of donor-specific antibodies in graft failure is becoming acknowledged, non-donor-specific antibodies may also be a confounder in the search for a broader repertoire of allo-antibodies affecting transplant outcome. It is obvious that progress cells for registration and collaboration to resolve confusion around test results. For this aim, the assessment of HLA antibodies should be included in hematopoietic stem cell transplantation management protocols.