A common laboratory finding in systemic autoimmune diseases is the presence of autoantibodies against intracellular autoantigens. Although their pathogenesis is not fully understood, autoantibodies are important tools for establishing diagnosis, classification, and prognosis of autoimmune diseases. Autoantibodies mainly target multicomponent complexes containing both protein antigens and (ribo)-nucleic acid(s), such as the spliceosome or Ro/La RNPs. In this review, we address the main characteristics and the clinical value of the main autoantibody types with respect to their disease association, and we describe the corresponding autoantigens, their biologic function, and their B-cell antigenic determinants (epitopes). The structural characteristics and clinical associations of these epitopes, and their utility as tools to investigate the autoimmune response, are discussed in detail. New insights into the pathogenetic role of epitopes in systemic autoimmunity are also examined. In this regard, using the defined structures of the B-cell antigenic epitopes, complementary epitopes can be designed according to the "molecular recognition" theory. These complementary epitopes can be used as probes to study pathogenetic and immunoregulatory aspects of the anti-idiotypic response. The origin of humoral autoimmunity and the spreading of the epitopes in systemic lupus erythematosus are also discussed. Finally, the ability of post-translational modifications to induce autoreactive immune attack via the generation of neo-epitopes is summarized.