Immunomodulation of islets aims at reducing graft immunogenicity and vulnerability to attack by immune competent cells and inflammatory mediators. Data from he International Islet Transplant Registry clearly establish this aspect as a central issue for the future of islet and endocrine cell transplantation. A primary target for graft immunomodulation is donor-derived costimulatory activity. Islet culture at 24 degrees C for 7 days is efficient in decreasing graft immunogenicity without affecting islet viability and can readily be used in clinical transplantation. Low-dose ultraviolet B irradiation may also help improving the effectiveness of immunosuppressive therapy. CTLA4lg appears to be a promising approach to target direct and indirect T-cell activation and may soon be applied to free or encapsulated islet transplants. A second target is the T cell, and strategies rely on a gene transfer approach to switch on T-cell apoptosis using Fas ligand, or to modulate T-cell populations with cytokines. Current results suggest that additional basic investigations are needed. Finally, the beta cell may be manipulated to improve its resistance to inflammatory mediators. Data using transfer of various genes (bcl-2, adenovirus E3, catalase, HSP70) have shown promising perspectives.