Screening for disease-specific autoantibodies may be useful in asymptomatic ANA-positive individuals as a means of evaluating the risk of developing a systemic autoimmune disease such as systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/DM), scleroderma (SSc), Sjögren's syndrome (SS), rheumatoid arthritis (RA), or primary biliary cirrhosis (PBC) in the future. In patients with known or suspected systemic autoimmune disease, a panel of disease-specific markers may help to establish a diagnosis and to assess the prognosis. The great strides in autoantibody testing over the last 20 years make it feasible to use specific autoantibody markers to improve diagnostic accuracy in systemic autoimmune disease. New technology enabling screening for multiple autoantibodies may further enhance the clinical usefulness of autoantibody testing, making it possible to diagnose autoimmune disease in its earliest stages and to intervene before serious end organ damage occurs.