Immunologically privileged sites express Fas ligand (FasL), which protects them from attack by activated T cells that express Fas and die upon contact with FasL. In an attempt to protect nonobese diabetic mice (NOD) from autoimmune diabetes, we made FasL transgenic NOD mice using the β cell-specific rat insulin-1 promoter. Surprisingly, these transgenic mice showed heightened sensitivity to diabetogenic T cells, which was due to self-destruction of β cells upon T cell-mediated induction of Fas. Fas-negative NOD^lpr/lpr animals were resistant to diabetogenic T cells and to spontaneous diabetes. Thus, induction of Fas expression on β cells and their subsequent destruction constitutes the main pathogenic mechanism in autoimmune diabetes.