Deletion of self-reactive clones of immature thymocytes by activation-induced death (AID) is thought to be the primary mechanism for the establishment of self-tolerance in the T-cell compartment. Recent evidence suggests that a genetically distinct but analogous process of AID in mature T cells is important in regulating peripheral immune responses. AID of peripheral T cells requires the expression of functional Fas and Fas ligand by the T-cell population. As qualitatively similar signals from the TCR are responsible for both T-cell expansion in inflammation and T-cell elimination by AID, regulating the balance between these opposing functions plays a crucial role in successful responses to pathogens and tumors while minimizing autoimmunity.