Rheumatoid arthritis (RA) is not only the most severe of all joint diseases but also the most common systemic autoimmune disease affecting approximately 1% of the world-wide adult population. RA is characterized by the presence of autoantibodies in serum and synovial fluid distinguishing the disease from other arthritides such reactive arthritis or osteoarthritis. Since the historical description of rheumatoid factor (RF), which is an autoantibody directed to immunoglobulin G, numerous additional autoantibodies have been discovered in sera of RA patients. These antibodies may be directed to cartilage components, stress proteins, enzymes, nuclear proteins and, most importantly, citrullinated proteins such as fibrin or vimentin. In contrast to other antibodies including RF, anti-citrullinated protein antibodies are targeted almost exclusively by RA patients thus being the most specific serological markers of RA. Even though most other antibodies are not used for diagnostics, they may contribute to the patholophysiology of RA by forming immune complexes in the joint. Furthermore, autoreactive T-cells in serum and synovial fluid may initiate or enhance the disease process via production of proinflammatory cytokines leading to autoantibody secretion, stimulation of macrophages and activation of bone resorbing osteoclasts. Identification of novel autoantigens, particularly citrullinated proteins, and the characterization of the cellular and molecular processes underlying the autoimmune reactions against them has provided new insights into the complex pathogenesis of RA. This has made possible the development of novel therapeutic concepts that may allow to treat the disease more effectively in its early stages where the chances are highest to interrupt the deleterious processes.