Immunologic incompatibilities between donor and recipient have limited the access to renal transplantation for many patients. Previously the presence of donor-specific alloantibodies directed against donor major histocompatibility complex (MHC) antigens or natural antibodies directed against donor ABO blood group antigens was considered an absolute contraindication to renal transplantation. However, with the current understanding of humoral immune responses, superior immunosuppressive agents, and improved diagnosis and treatment of antibody-mediated rejection, renal transplantation can be safely performed with outstanding results despite the presence of donor-specific antibody. In this review we discuss the biology of antibody-mediated rejection and sensitization. We discuss the diagnostic tests necessary to characterize the type, affinity, and avidity of the donor-directed antibodies. Current methods for performing renal transplants across ABO and human leukocyte antigen (HLA)-sensitized barriers are covered, including the potential morbidities. The rest of the review focuses on advances in managing these antibodies to increase the likelihood of receiving a deceased donor kidney or allow transplantation from a living donor against whom one has a prohibitive antibody.