Introduction: Acute antibody-mediated rejection (AMR) in renal-transplant recipients is generally less responsive to conventional antirejection therapy and has a worse prognosis than acute cellular rejection. Areas covered: This review provides a broad understanding of the pathogenesis of AMR, recent advances in its therapy, and future directions. Conventional therapeutic approaches to AMR have minimal impact on mature plasma cells, the major source of antibody production. Emerging therapies include bortezomib, a proteasome inhibitor, and eculizumab, an anti-C5 antibody. In several reports, bortezomib therapy resulted in prompt reversal of rejection, decreased titers of donor-specific antibodies (DSA), and improved renal allograft function. Eculizumab also reversed AMR and prevented its development in patients with high post-transplantation DSA levels. Expert opinion: Despite the small sample size and lack of controls, these studies are encouraging, and although larger studies and long-term follow-up are needed, bortezomib and eculizumab may play a major future role in AMR therapy.