Recent evidence has confirmed that sera from most systemic sclerosis (SSc) patients contain one of three mutually exclusive, SSc-associated autoantibodies (anti-RNA polymerase III, anti-topoisomerase I, or anti-centromere antibodies). Each is associated with the presence of particular clinical features and certain human lymphocyte antigen (HLA) alleles. Based on the available data the most likely model is for the existence of three distinct disease processes, each with certain key pathologic features. In turn, each pathologic state is responsible for characteristic symptoms, and leads to the production of a distinctive set of modified autoantigens. Certain cryptic epitopes are consequently produced by antigen-presenting cells, and are effectively presented according to the available HLA molecules, with subsequent HLA-restricted autoantibody production. Thus, while not directly involved in disease pathogenesis, SSc-associated autoantibodies appear to be reliable reporters of disease-specific pathologic phenomena, and may prove valuable pointers toward the etiopathogenesis of the different subtypes of SSc.