On April 23, 1951, a 30-year-old woman received the first intentional ABOi (ABO incompatible) renal transplantation in Boston. At that time, it was commonly believed that intensely rinsing the graft to remove blood would be sufficient to overcome any immunological problems associated with blood type incompatibility. However, when the abovementioned patient and another ABOi transplant recipient died within a month, Humes and colleagues arrived at the same conclusion: "We do not feel that renal transplantation in the presence of blood incompatibility is wise." In the decades that followed, we learned that the oligosaccharide surface antigens representing the ABO-blood group antigens are expressed not only on erythrocytes but also on cells from various tissues, including the vascular endothelium. The growing gap between organ demand and availability has sparked efforts to overcome the ABO barrier. After its disappointing results in the early 1970s, Japan became the leader of this endeavor in the 1980s. All protocols are based on 2 strategies: removal of preformed antibodies with extracorporeal techniques and inhibition of ongoing antibody production. Successful ABOi renal transplantation became possible with the advent of splenectomy, new immunosuppressive drugs (e.g., rituximab, a monoclonal antibody against CD20), and extracorporeal methods such as antigen-specific immunoadsorption. This review summarizes the underlying pathophysiology of ABOi transplantation and the different protocols available. Further, we briefly touch potential short- and long-term problems, particularly the incidence of infectious complications and malignancies, that can arise with high-intensity immunosuppressive therapy.