OBJECTIVE Antibody-mediated rejection is responsible for up to half of acute rejection episodes in kidney transplant patients and more than half of late graft failures. Antibodies cause acute graft abnormalities that are distinct from T cell-mediated rejection and at later times posttransplant, a distinct pathologic lesion is associated with capillary basement membrane multilayering and glomerulopathy. Despite the importance of donor-reactive antibodies as the leading cause of kidney graft failure, mechanisms underlying antibody-mediated acute and chronic kidney graft injury are poorly understood. Here, we review recent insights provided from clinical studies as well as from animal models that may help to identify new targets for therapy. RESULTS Studies of biopsies from kidney grafts in patients with donor-specific antibody versus those without have utilized analysis of pathologic lesions and gene expression to identify the distinct characteristics of antibody-mediated rejection. These analyses have indicated the presence of natural killer cells and their activation during antibody-mediated rejection. The impact of studies of antibody-mediated allograft injury in animal models have lagged behind these clinical studies, but have been useful in testing the activation of innate immune components within allografts in the presence of donor-specific antibodies. CONCLUSIONS Most insights into processes of antibody-mediated rejection of kidney grafts have come from carefully designed clinical studies. However, several new mouse models of antibody-mediated kidney allograft rejection may replicate the abnormalities observed in clinical kidney grafts and may be useful in directly testing mechanisms that underlie acute and chronic antibody-mediated graft injury.