Detection of rheumatoid factor (RF) in the serum of patients with rheumatoid arthritis (RA) was one of the first indications of autoimmunity in RA. The role of RF in the diagnosis of RA has been well-documented, but it has suboptimal sensitivity and specificity. Although patients with RF-positive RA generally have more severe disease than those with RF-negative RA, RF is not a reliable predictor of disease severity in individual patients. Multiple other autoantibodies have been found in RA, with recent interest focused on those directed at cyclic citrullinated peptides. Panels of autoantibodies may ultimately prove useful in preclinical diagnosis and prediction of clinical course in patients with RA and other forms of arthritis, and provide insights into the pathogenesis of the disease.