Recent studies have significantly advanced our understanding of the physiological and pathogenic functions of Fas and Fas ligand (FasL) in vivo. In particular, roles for Fas-FasL interactions both in the induction and regulation of organ-specific autoimmune diseases have been defined and in some cases the specific targets and effectors of these interactions have been identified. Understanding the dynamic role of the Fas-FasL pathway in autoimmunity will provide insight into how best to modulate this interaction to achieve therapeutic benefits.