The prevalence of autoimmune disorders is increasing steadily and there is no permanent cure available. Immunomodulation through repeated exposure of antigens, known as antigen-specific immune tolerance or antigen-specific immunotherapy (ASI), is a promising approach to treat or prevent autoimmune disorders. Different optimization protocols (immunization routes, delivery systems, and approaches) are being developed to implement ASI against self-proteins. Including appropriate adjuvants, altered peptide ligand, and using multipeptides are approaches that can be used to specifically target autoimmunity. This review explores various ASI application methods, including different routes of antigen-specific sensitization, delivery systems, immunomodulators containing specific antigens, and other targeted approaches that have been successfully demonstrated to have therapeutic effects on autoimmune diseases. © 2018 Elsevier Ltd.