In contrast to solid organ transplantation (SOT), ABO-histo blood group incompatibility is of minor importance for hematopoietic stem cell transplantation (HSCT). Patients receiving ABO-incompatible HSCT are at an increased risk for immune-mediated hematological complications including immediate and delayed hemolysis, late red blood cell engraftment and pure red cell aplasia, but seem not to have a worse overall survival or increased transplant-related mortality. This review gives an overview of the immunological mechanisms leading to complications associated with ABO-incompatible HSCT and describes approaches to prevent them. The current organ shortage in SOT stimulates the exploration of new strategies to expand the donor pool including ABO-incompatible SOT and xenotransplantation. Here, we discuss the hypothesis that ABO-incompatible transplantation may be viewed as a human in vivo model for the humoral immune mechanisms of antigen-mismatched transplantation. ABO-incompatible HSCT and SOT provide excellent possibilities to analyze graft accommodation and transplantation tolerance. Understanding the underlying mechanisms of graft survival in ABO-incompatible transplantation may facilitate new strategies to overcome the immunological barriers in SOT and xenotransplantation.