Transplantation is the treatment of choice for end-stage renal failure and a life-saving treatment for failure of other major organs. Improvements in surgical techniques, histocompatibility testing, and immunosuppressive drugs have significantly improved both patient and graft survival. However, there are formidable barriers to the successful transplantation of patients who possess HLA-specific antibodies. Sensitized patients wait longer for a transplant and, once transplanted, experience more rejection episodes and have decreased graft survival compared to non-sensitized recipients. Improvements in HLA-specific antibody detection have expanded the donor pool available to sensitized patients and desensitization protocols designed to reduce the breadth and amount of HLA-specific antibody have found increased success during the last decade. Determining the appropriate course of treatment for the sensitized patient requires accurate immunologic characterization and clinical assessment of the patient. Together, the transplant physician and histocompatibility expert must determine what constitutes a compatible donor and assess the patient's risk for a particular transplant. Thus, sensitization to HLA antigens is a problem for the patient, the transplant physician, and the histocompatibility laboratory.