One of the major challenges in the current era of organ transplantation is to find suitable organs for highly sensitized patients. Different approaches have been successful in a proportion of the patients. Several organ exchange organizations are currently implementing an acceptable mismatch program similar to the one developed by Eurotransplant. The basis of such a program is the accurate definition of those HLA antigens or epitopes toward which the patient did not form antibodies. Donors, who are compatible with the combination of the HLA type of the recipient and these acceptable HLA mismatches, will have a negative crossmatch and are allocated with the highest priority to the highly sensitized patient. Such an approach has shown to increase the transplantation rate with excellent results. Another possibility to find a crossmatch negative donor for highly sensitized patients, who have a positive crossmatch with their potential living donor, is via a (national) paired kidney exchange program. Alternative approaches aim at desensitization of the patient in order to be able to transplant the patient with a donor despite the original crossmatch was positive. Recent protocols include the use of intravenous immunoglobulin in combination with an anti CD20 monoclonal antibody (Rituximab). In order to eliminate the antibody producing plasma cells as well, Bortezomib is recently proposed as a possible agent for future desensitization protocols. As none of these approaches are successful in all patients, a comprehensive use of a combination of these strategies seems the way to go.