The diagnosis of antibody-mediated rejection (AMR) has presented a challenge due to the pleiomorphic immunologic responses that represent the condition. A consensus with regard to its pathological diagnosis continues to evolve. Due to an increasing number of sensitized patients undergoing heart transplantation, its incidence appears to be on the rise and the condition is associated with worse outcomes than acute cellular rejection. Treatment of AMR is also more difficult and response to increases in conventional immunosuppression is often limited. Risk factors for AMR include the use of ventricular assist devices, prior exposure to blood products, allografts and multiparity. Detection of alloantibodies with a high specificity and sensitivity allows risk stratification of recipients at potential risk of AMR. Desensitization and AMR treatment strategies are focused on several therapeutic targets, including suppression of T and B cells and elimination or inhibition of circulating antibodies.