AbstractThe overall shortage of appropriate donor organs has prompted transplant physicians and surgeons to consider using organs from other nonhuman species. The shortage of appropriate human donor hearts for newborn recipients is especially severe. Presently, the pig appears to be the most appropriate source for organs. Humans and baboons uniformly develop high titers of complement‐fixing (IgM) anti‐pig xenoantibodies, resulting in complement‐mediated hyperacute rejection (HAR) of pig organs transplanted into mature baboons within minutes to hours. In contrast, newborn humans and baboons do not have high titers of anti‐pig IgM xenoantibody, and consequently pig cardiac xenografts transplanted into newborn baboons do not undergo HAR. Rather, these organs are rejected at days 3 to 4 by a distinctive immunologic process that involves natural killer cells and macrophages. With the addition of cyclosporine‐based triple immunosuppression, this process is reduced and graft life is prolonged to 6 to 7 days. This therapy, however, is not sufficient to prevent the induced humoral response to the graft, and the organs are rejected by antibody‐ and complement‐dependent mechanisms. Future treatment strategies to reduce this humoral response must incorporate immunodepletion columns, soluble complement‐inhibiting agents, and additional anti‐B lymphocyte agents. These strategies, in conjunction with the use of transgenic pig organs that express human membrane‐bound complement regulatory proteins or reduced xenoantigenic epitopes could further prolong graft life. Clinical trials are being formulated that would utilize pig organs as a “bridge,” sustaining a newborn human in need of a heart transplant until an appropriate donor is located.