Since the first identification of self-reactive antibodies in systemic lupus erythematosus and other systemic autoimmune rheumatic diseases, many autoantibodies have been identified as useful probes in molecular and cell biology and as diagnostic and prognostic biomarkers in clinical immunology. Among the autoantigens, double-stranded desoxoribonucleic acid (dsDNA), the Smith antigen (Sm), ribonucleoproteins (RNP), Scl-70 (topoisomerase I), proliferating cell nuclear antigen (PCNA), and others were described as serologic hallmarks in the diagnosis of systemic autoimmune rheumatic diseases. Despite these advances in identifying autoantibody markers, a number of challenges and controversies persist concerning their origin, clinical usefulness and relevance. These include the association between anti-ribosomal P antibodies and clinical features in systemic lupus erythematosus, the disease specificity of several autoantibodies (i.e. chromatin, Jo-1, alpha-fodrin, topo I and CENP), the relationship between the SS-A/Ro52 and SS-A/Ro60 autoantibody system(s) and the detection of anti-RNP/Sm and anti-fibrillarin antibodies.