In recent years, the deleterious clinical consequences of recipient de novo alloantibody production against HLA antigens from human organ allografts have been extensively investigated. In kidney transplantation, the identification of the complement C4d fragment in peritubular capillaries as a specific marker for humoral rejection has helped to define and characterize distinct clinical alloantibody-mediated syndromes. This knowledge is relevant for patient management as new therapeutic strategies to remove and control anti-donor antibody production, particularly in the setting of acute humoral rejection, have been reported. For recipients of nonrenal organ allografts such as heart transplant recipients, de novo anti-HLA alloantibody may also be important, although more studies are needed before clear guidelines can be proposed.