Desensitization has transformed kidney transplantation for patients with high immunologic risk by lowering or removing antibodies that would otherwise cause graft loss. Pre- and peri-transplant plasmapheresis (therapeutic plasma exchange) with low-dose intravenous immunoglobulin (IVIG), sometimes combined with B-cell depletion (rituximab) or newer agents (imlifidase, bortezomib, daratumumab), is standard for HLA- or ABO-incompatible living and deceased donor transplants. Plasmapheresis is also first-line therapy for antibody-mediated rejection and for recurrent focal segmental glomerulosclerosis (FSGS), where early, intensive sessions can induce remission; resistant cases may benefit from lipoprotein apheresis. Highly sensitized patients are identified by elevated panel reactive antibody (PRA/cPRA) levels; allocation systems now prioritize these candidates, but desensitization remains key when compatible organs are unavailable. Pediatric protocols aim to minimize apheresis burden while maintaining good graft survival. In parallel, xenotransplantation—especially gene-edited pig kidneys—is entering early human trials; here, preemptive or rescue plasmapheresis/IVIG has shown utility in controlling anti-pig antibody responses. Emerging strategies target long-lived plasma cells, complement pathways, and precise antibody monitoring to make incompatible and xenogeneic transplantation safer and more durable.