After delayed-type hypersensitivity and T cell cytotoxicity, the production of alloantibodies is the third effector mechanism contributing to graft injury. Histological characterization of antibody-mediated rejection and the detection of donor-reactive antibodies have highlighted the role of humoral immunity in acute and chronic rejection. A potential way of achieving central B cell tolerance is to induce complete chimerism with a myeloablative regimen and bone marrow transplant. However, nonmyeloablative regimens have been developed to create a state of "mixed chimerism" in patients without hematologic malignancies. Other strategies targeting B cells have been developed for the management of "high risk" clinical situations, including highly sensitized patients and transplantation with a positive crossmatch. These strategies have been extended to ABO incompatible transplantations and xenotransplantations. We will review therapeutic regimens that allow the removal or neutralization of pathogenic antibodies (immunoadsorption, plasmapheresis, intravenous globulins) and the blockade of memory B cell proliferation and differentiation into plasmocytes, including cyclophosphamide, the tacrolimus/mycophenolate mofetil combination, and anti-CD20 antibodies.