The present disclosure relates to methods of treating or reducing the risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a subject in need thereof (e.g., a human) by administering an antagonist that targets CD40 or CD154, such as an anti-CD40 antibody or an antigen-binding fragment thereof (e.g., a humanized anti-CD40 antibody or antigen-binding fragment thereof. The transplant may be an allogeneic or xenogeneic transplant (e.g., a cell, tissue, or organ or portion thereof).