Antibody-mediated rejection (AMR) is now recognized as an important clinical complication of pediatric and adult cardiac transplantation. In addition to causing graft dysfunction, it has been associated with the accelerated development of transplant vasculopathy and graft loss. It can occur early after transplantation, especially in presensitized patients, but late-onset antibody-mediated rejection is now encountered more frequently. It is characterized by microvascular injury centered on the myocardial interstitial capillaries. The diagnosis is currently based on histopathologic and immunophenotypic criteria without reference to clinical status or presence of circulating donor-specific antibodies. The current International Society for Heart and Lung Transplantation grading scheme incorporates the constellation of histopathologic and immunopathologic findings and is now widely utilized for the diagnosis and reporting of AMR.