Autoimmune diseases are distinct clinical syndromes characterized by various alterations in normal immune responsiveness, such that there is a loss of tolerance to particular host constituents. In most cases, despite years of intense investigation, the etiopathogenic antigens initiating these systemic inflammatory conditions remain undefined. However, a great deal has been learned about the changes in components of the immune response relevant to the propagation and sustenance of these often chronic disorders. In addition, various hormonal, environmental, physiologic, and other influences that affect their expression have been identified. The expression and ultimate clinical outcome of autoimmune diseases usually relate to inflammation-related damage to the target organ with subsequent dysfunction. Certain immune conditions, such as autoimmune thyroid disease, largely affect a single organ, whereas others, such as systemic lupus erythematosus, heterogeneously affect sundry organ systems. Autoantibodies directed against normal host antigens are a common feature of many autoimmune diseases. In some cases they are pathogenic, whereas in others they serve as markers for organ involvement or outcomes. Clinical descriptions of autoimmune diseases date back many decades in some cases. Recent efforts at formulating classification criteria have allowed clearer distinctions and more accurate stratification. Greater understanding of the immunopathogenesis of autoimmune conditions has led to the development and introduction into the clinic of novel immunomodulatory therapies and treatment paradigms that have substantially improved the outcomes for patients affected by these serious conditions.