Owing to the shortage of deceased donors in Japan, since 1989, we have performed ABO-incompatible kidney transplantation (ABO-IKTx) to expand the indication for living donor kidney transplantation. During the past two decades, about 2000 ABO-IKTxs were performed. Since 2001 the success rate for these kidney transplants has reached 96% for 1-year, 91% for 5-year and 83% for 9-year graft survival, similar to outcomes of ABO-compatible kidney transplantation (ABO-CKTx). This dramatic improvement in results means that ABO-IKTx has become accepted as a therapeutic alternative for end-stage renal failure. Today ABO-IKTx accounts for approximately 30% of all living donor kidney transplantations performed in Japan.We have been making a lot of efforts to elucidate the mechanism of acute antibody-mediated rejection in ABOI-KTx in order to overcome the ABO barrier and to improve the outcome. From careful and precise clinical observations, proteomic analysis of ABO histo-blood group antigens in graft endothelial cells and deep insight into immunology and biology, we have reached the hypothesis that the structural difference of ABO histo-blood group antigens and de novo corresponding antibody production would be the key and keyhole of the development of acute AMR in ABOI-KTx. Preoperative desensitization therapy would be the best solution for the suppression of acute AMR and graft loss, which is now widespread and improves the outcome. © 2013 Elsevier Inc.