The endothelial cells of the cardiac vasculature express human leukocyte antigens (HLA) and others, such as vimentin and major histocompatibility complex (MHC) class I-related chain A (MICA), and appear to be primary targets of cell-mediated and humoral immune responses after heart transplant (HTx). Circulating antibodies mediate rejection through complement activation and fixation on graft endothelium, thereby predisposing the patient to graft loss, accelerated cardiac allograft vasculopathy, and death. The rate of allosensitized patients (patients with circulating antibodies against donor antigens) on waiting lists is increasing as a consequence of growing numbers of retransplants and assist-device implantations. Allosensitization is a consequence of exposure to disparate HLA molecules during pregnancy, blood/platelet transfusions, or after cardiac repairs with homograft material, but may occur in some patients even without any of these triggers from unknown reasons.