The beneficial effects of HLA matching in renal transplantation have been known for decades, and an allocation system that emphasizes Class II matching has been proposed. Recent data have demonstrated that the development of dnDSA, particularly against Class II HLA antigens, is a major cause of renal transplant loss. The histopathology of chronic antibody-mediated rejection is characterized by immune injury to the endothelium of the glomeruli and peritubular capillaries. The early phases of injury occur subclinically, many months before graft dysfunction, providing the opportunity for the optimization of current therapies and the evaluation of new treatment strategies. Risk factors for dnDSA development include Class II HLA mismatching, patient nonadherence to IS medications, and prior cellular rejection. Because the current treatment of chronic antibody-mediated rejection is largely unsatisfactory, prevention strategies that attempt to minimize the known risk factors should be adopted. © 2014 Lippincott Williams and Wilkins.