Longevity of the intestinal recipients and allogra functions is commonly threatened by the sustained risk of destructive alloim­munity and long-term adverse eects of immunosuppression. It is tempting to believe that the relatively high immunogenicity of the vis­ceral allogra is the result of a constant dynamic interaction between adaptive and innate immunity. A strong association has been found between circulating donor-specic anti-HLA antibodies and gra loss due to chronic rejection. In addition, mutations of nucleotide-binding oligomerization domain–containing 2 (NOD2) genes were incrimi­nated as a signicant risk factor for gra loss as a result of impaired expression of epithelial-derived antimicrobial peptides with disrup­tion of the epithelial barrier and subsequent inammatory cell inltra­tion into the gra intestinal wall. Until eective tolerance protocols are within reach, recipient pretreatment with antilymphoid preparations and induction therapy with an anti–B cell proteasome inhibitor (bort­ezomib) for patients with preformed antibodies have been introduced to overcome such a sinister barrier. Other potential therapeutic strat­egies include cell therapy, co-stimulation blockade with belatacept, anticomplement treatment with anti-C5 antibody or a C1-inhibitor, and seeking a negative virtual cross-match or utilizing a desensitiza­tion protocol for potential recipients with preformed antibodies.