Organ-specific autoimmunity is characterized by the accelerated loss of selected cell types, resulting in specific tissue destruction and disease. The role of different genetic or environmental factors in initiating the autoimmune reactivity is still unclear. However, novel mechanisms responsible for tissue destruction have recently been revealed. Here, Ruggero De Maria and Roberto Testi propose that Fas ligand may represent a common weapon during the destructive phase of organ-specific autoimmunity.