Perhaps one of the most elusive areas of study in autoimmunity has been identifying the self-antigens that initially trigger the development of autoimmune responses. Recent work in this area has demonstrated that a number of biochemical modifications that arise in proteins after their translation induce autoimmune responses to otherwise ignored self-proteins. This article will describe those autoimmune diseases in which posttranslational modifications may play a role in initiation of disease, as well as identify how these modifications arise and contribute to the breakdown of immune tolerance. Lastly, we will address how posttranslational modifications in self-antigens affect current diagnostic techniques and the development of immunotherapies for autoimmune diseases.