Antibodies to donor HLA (human leukocyte antigen) and/or ABO antigens were a contraindication to transplantation of most organs for decades. Desensitization protocols have shown the ability to produce reduction of such antibodies sufficient to achieve a successful transplantation. The two major protocols in use are high-dose IVIg or plasmapheresis with low-dose IVIg. The protocols differ in the basic treatment and, to some degree, in their application, but both use standard immunosuppressive agents as well as more recently developed adjunctive agents such as cell-depleting antibodies. Graft and patient survival with both types of protocol are comparable to that of non-sensitized patients, although desensitized patients do have a higher incidence of antibody-mediated rejection (AMR). Antibodies to donor antigens may persist after transplantation, and while the initial antibody titer represents the level of difficulty for successful desensitization, the strength of antibodies that persist after transplantation reflects the risk of AMR. Current protocols do not eliminate B cell clones specific for donor HLA; therefore, desensitized patients remain at an increased risk of antibody rebound if patients experience pro-inflammatory events. Therefore, ongoing antibody monitoring is crucial for early detection of antibody-mediated graft injury. Importantly, the results of numerous programs show that ABOi- and HLA-positive crossmatch renal transplantation, with proper desensitization, can be performed successfully. Further, in addition to increasing the rate of transplantation among sensitized patients, desensitization is providing insight into immunoregulatory processes and may provide information useful in diseases involving immune dysfunction.