The mechanism by which tolerance is broken in the induction of autoimmunity is unknown. Simple, well-characterized antigens suggest that molecular complementarity may play a key role in breaking tolerance. Experimental allergic encephalomyelitis can be induced using myelin basic protein combined with muramyl dipeptide. These molecules bind specifically to each other. Insulin antibodies can be induced when insulin is combined with glucagon, to which it binds. These cases suggest that molecular complementarity may alter the processing of "self" proteins. Antigenic complementary yields molecularly complementary immune responses (i.e., idiotypic-anti-idiotypic), undermining immune system regulation. In addition, complementarity insures that the antibodies (or T cells) directed against one antigen will molecularly mimic the other antigen, and vice versa, so that "self" and "nonself" will be confused. If at least one complementary antigen mimics a "self" protein, then an unregulated, self-sustaining immune response against tissue results. This testable theory of antigenic complementarity in autoimmunity is reviewed.