The need for permanent, nonspecific, and potentially harmful immunosuppression remains a major obstacle for islet transplantation. The response of a type 1 diabetic recipient to an islet graft includes a specific allogenic immune response and the recurrence of autoimmunity. Free or encapsulated in an immunoisolation device, islet cells are exposed to immune aggression, initiated by donor antigen-presenting cells or by indirect, host antigen-presenting cell-mediated antigen presentation. CTLA4-Ig is a genetically engineered fusion protein of human CTLA4 and the IgG 1 Fc region. It prevents T-cell activation by binding to human B7, which costimulates T cells through CD28. Interesting data were reported in experimental islet transplantation, suggesting that CTLA4-Ig may be slightly but significantly beneficial to islet allograft survival, although studies in autoimmune diabetes are scarce. The main limitations include transient and low levels of expression when CTLA4-Ig is delivered locally, a predominant effect on the direct recognition pathway, and the lack of effect on memory cells. Clinical trials in islet transplantation could be discussed in nonuremic patients, with steroid-free and anticalcineurin-free regimens, in combination with another costimulation blocker, rapamycin, and an anti-interleukin 2 receptor antibody, and with a strategy directed against the recurrence of autoimmunity.