Long before the RNA degrading exosome was first described in the yeast Saccharomyces cerevisiae, the use of autoantibodies found in the sera of certain autoimmune patients allowed the identification of a complex of polypeptides which later appeared to be the human exosome. Today, the most extensively documented association of the exosome with disease is still its targeting by the immune system of such patients. The highest frequency of autoantibodies to components of the exosome complex is found in polymyositis-scleroderma overlap patients and therefore the exosome is termed PM/Scl autoantigen in the autoimmune field. More recently, one of the core components of the exosome was identified as a protein associated with chronic myelogenous leukemia. In this chapter we will describe the identification of the PM/Scl autoantigen from a historical perspective, discuss our current knowledge on the occurrence of autoantibodies to exosome components in autoimmune diseases and end with the data that connect the exosome with cancer.