In this two-part series, Argyrios N. Theofilopoulos summarizes the current state of affairs in the field of autoimmunity. Part I integrates the collective mechanistic theories of autoimmune diseases. The most straightforward explanation to emerge with regard to organ-specific diseases is the concept that these are caused by inappropriate, yet conventional, immunological responses against self-antigens for which tolerance has never been established. A similar mechanism may be operative in systemic autoimmunity, but other abnormalities such as defects in the apoptosis machinery may also be invoked. Part II will address the genetic contributions predisposing to autoimmune syndromes.