More than one quarter of renal allograft recipients are susceptible to antibody-mediated rejection (AMR). There are well-established therapies (plasmapheresis, immunoadsorption, intravenous immunoglobulin, rituximab, rATG, splenectomy) to overcome AMR in the short term. However, the usual persistence of donor-specific antibodies (DSA) post-transplanta-tion rather than to produce an accommodation state is associated to development of trans-plant glomerulopathy and then to a progressive renal allograft function deterioration. Thus, novel strategies are needed to prolong graft survival in this setting. First of all, an appropriate maintenance immunosuppression is needed to avoid the activation of direct and indirect anti-gen presentation pathways in combination with reliable immunomonitoring methods. Among new approaches, experimental studies suggest that strategies like anti-C5 mAb addressed to induce an accommodation state in endothelial cells may be useful. Costimulation blockade, particularly interference of the CD40-CD154 pathway, would be of relevance. Interference of CD40 by siRNA technology is able to induce a protective phenotype (anti-inflammatory, anti-apoptotic, anticoagulant) in endothelial cells in conjunction with fully avoidance of adaptative humoral immunity in the host.