© 2020 Bentham Science Publishers. The organ shortage for kidney transplantation remains a challenging issue worldwide. Incompatibility between donor-recipient pairs, commonly occurring among transplant candidates who were sensitized from prior antigen exposure, serves as a significant barrier to kidney transplantation. In efforts to overcome this obstacle, living and deceased donor kidney transplantation across human leukocyte antigen barriers following desensitization has been pursued via positive crossmatch transplantation. The goal of desensitization therapy is to remove or denigrate donor-specific alloantibodies prior to transplantation in order to permit transplantation across the human leukocyte antigen barrier and prevent rejection. Various desensitization regimens have been utilized, including the use of plasmapheresis, intravenous immunoglobulin, and or immunoadsorption. Although long-term allograft outcomes for positive crossmatch kidney transplantation following desensitization therapy have been shown to be inferior to compatible transplantation, particularly with increasing strength of the crossmatch, there is an estab-lished survival benefit for positive crossmatch transplant recipients compared with remaining on the transplant waitlist. However, positive crossmatch transplantation may confer higher risks of infection and malignancy. Despite the fact that some of these heightened risks, positive crossmatch transplantation has also been demonstrated to have cost-savings compared with remaining on dialysis and may, therefore, be a cost-effective treatment option for sensitized patients who would face long waiting times and may never be able to achieve compatible transplan-tation. This review highlights both the risks and benefits of positive crossmatch transplantation and its role in the broader field of kidney transplantation.