An epitope is an antigenic determinant, or a site on the surface of an antigenic molecule, to which a single antibody binds. Epitope spreading (ES) refers to the development of an immune response to epitopes distinct from, and noncross-reactive with, the disease-causing epitope. Diversification, or the ability of the immune system to attack multiple targets on a pathogen has obvious advantages. Here we review some of the evidence regarding its role in autoimmunity, in humans and in animal disease models. We consider the implications of ES on the development of highly specific therapies for autoimmune disease. We stress that pathogenic ES probably occurs in the context of inherent abnormalities in control mechanisms for the prevention of autoimmunity or other genetic predisposing factors.