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Interest in the role of donor-specific human leukocyte antibodies in liver transplantation has been rekindled recently. Emerging evidence suggests that these antibodies may cause injury to the liver allograft. Here we review the clinical literature, highlight controversial results, and propose a path forward for the definition and better understanding of antibody-mediated injury to the liver. Liver Transpl 20:514–527, 2014. © 2014 AASLD.