Proteins are complex organic molecules susceptible to numerous post-translational modifications occurring spontaneously during aging or as a consequence of physiologic or pathologic processes. Antigenicity and interactions of proteins with components of the immune system may be profoundly affected by post-translational modifications. Thus, modified self-antigens may be absent (not-tolerated) during early T-cell selection and trigger reactions by the immune system as they arise later in life. In turn, this may play a role in the initiation and pathogenesis of autoimmune diseases. This Review article presents an overview of protein modifications that have been shown to affect antigenicity and presentation of protein antigens in autoimmune diseases. The relevance of these observations is discussed, and the implications for future prophylactic and therapeutic interventions are outlined.