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Antibody-mediated rejection (AMR) currently represents one of the main problems for clinical management of heart transplant because of its diagnostic complexity and poor evidences supporting treatments.Disorder-based diagnosis is a cornerstone in defining AMR. The limitations of the current classification have been partially overcome by novel studies improving the description of the immune-pathological graft abnormalities, and by new molecular approaches allowing a better understanding of the mechanisms behind AMR and of its relationship with cellular rejection and chronic vasculopathy. In-depth characterization of donor-specific antibodies showed to provide additional prognostic information and guide for treatment. Clinical relevance of AMR is bound to appropriate detection of graft dysfunction. In addition to traditional longitudinal evaluation by echocardiogram, cardiac magnetic resonance and detection of cell-free DNA may represent novel sensitive markers for graft injury that could prompt treatment before dysfunction becomes clinically manifest.Despite improvements in the diagnostic process, therapeutic strategies made little progress in addition to the consolidation of practices supported by limited evidences. Novel complement inhibitors appear promising in changing this scenario. Nevertheless, collaborative multicenter studies are needed to develop standardized approaches tailored to the highly variable clinical and laboratory features of AMR.