There are many highly sensitized patients on the kidney waiting lists of organ exchange organizations because it is difficult to find a crossmatch negative cadaver kidney for these patients. Recently, several protocols have been developed to remove the donor-specific human leukocyte antigen (HLA) antibodies from the serum of these patients before transplantation. These approaches, including the use of intravenous immunoglobulins, plasmapheresis and immunoglobulins (plasmapheresis-cytomegalovirus-immunoglobulin), and immunoabsorption, seem to lead to a certain success rate, although the additional immunosuppression necessary to remove and control the production of donor-specific alloantibodies may have its impact on the short-term (infections) and long-term (incidence of cancer) immune surveillance. Furthermore, some of these therapies represent a considerable financial burden for patients and society. In the present report, we advocate selection of crossmatch negative donors on the basis of the Acceptable Mismatch Program, as the first and best option for highly sensitized patients to undergo transplantations. No additional immunosuppression is necessary, and graft survival in this group of "difficult" patients is identical to that of nonsensitized recipients. Because the nature of the HLA polymorphism does not allow all patients to profit from this approach, removal of circulating HLA antibodies can be considered as a rescue therapy for those patients for whom the Acceptable Mismatch Program does not give a solution.