As the consequences of autoimmunity are so damaging to an individual, both deletional and non-deletional forms of T-cell tolerance are observed in the thymus as well as the periphery. Although the relationship between these types of tolerance is not clear, recent studies in vivo and in vitro have begun to identify the cellular and molecular interactions involved. Whereas thymic development must account for both positive and negative selection, it is now apparent that T-cell responses in the periphery must also strike a balance between the generation of effector function and activation-induced tolerance.