Autoantibodies directed against nuclear, nucleolar, and a number of cytoplasmic components are described in the sera of scleroderma patients. Early studies of autoantibodies that relied on cryopreserved sections of rodent organ substrates showed that approximately 50% of scleroderma patients had anti-nuclear antibodies (ANA). More recent studies that have used tissue culture cell substrates have shown that up to 98% of scleroderma patients have a positive ANA. In all of these studies, the presence of different patterns of staining have suggested that scleroderma sera reacted with a variety of intracellular antigens. The use of molecular and immunochemical techniques has now shown that over 20 intracellular autoantigens are targets of autoantibodies in scleroderma sera. Clinical studies have shown that these autoantibodies are important diagnostic and prognostic markers in scleroderma. In the future, autoantibody testing may be used to monitor the patient's response to immunological therapies.