The current organ shortage in transplantation medicine stimulates the exploration of new strategies to expand the donor pool including the utilisation of living donors, AB0-incompatible grafts, and xenotransplantation. Preformed natural antibodies (Ab) such as anti-Gal or anti-A/B Ab mediate hyperacute graft rejection and thus represent a major hurdle to the employment of such strategies. In contrast to solid organ transplantation (SOT), AB0 blood group incompatibilities are of minor importance in haematopoietic stem cell transplantation (HSCT). Thus, AB0 incompatible HSCT may serve as an in vivo model to study carbohydrate antigen (Ag)-mismatched transplantations such as AB0-incompatible SOT or the effect of preformed Ab against Gal in xenotransplantation. This mini-review summarises our clinical and experimental studies performed with the support of the Swiss National Science Foundation program on Implants and Transplants (NFP-46). Part 1 describes data on the clinical outcome of AB0-incompatible HSCT, in particular the incidence of several immunohaematological complications, acute graft-versus-host-disease (GvHD), and the overall survival. Part 2 summarises the measurements of anti-A/B Ab in healthy blood donors and AB0-incompatible HSCT using a novel flow cytometry based method and the potential mechanisms responsible for the loss of anti-A/B Ab observed following minor AB0-incompatible HSCT, ie the occurrence of humoral tolerance. Part 3 analyses the potential of eliminating Gal expression as well as specific complement inhibitors such as dextran sulfate and synthetic tyrosine analogues to protect porcine endothelial cells from xenoreactive Ab-mediated damage in vitro and in a hamster-to-rat heart transplantation model. In conclusion, due to similarities of the immunological hurdles of AB0 incompatible transplantations and xenotransplantation, the knowledge obtained from both fields might lead to new strategies to overcome humoral rejection in transplantation.