Summary: A number of autoimmune diseases, including multiple sclerosis, are mediated by self-reactive T cells that have escaped the deletional mechanisms of central tolerance. Usually, these T cells are kept at bay through peripheral tolerance mechanisms, including regulation through coinhibitory receptors and suppression by regulatory T cells. However, if these mechanisms fail, self-reactive T cells are activated and autoimmune responses ensue. This review outlines how the coinhibitory receptors CTLA-4 (cytotoxic T-lymphocyte antigen-4), PD-1 (programed death-1), Tim-3 (T-cell immunoglobulin- and mucin domain-containing molecule 3), and TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains) act at different checkpoints to inhibit autoreactive T cells and suppress the development of central nervous system autoimmunity. Loss of each of these receptors predisposes to autoimmunity, indicating a non-redundant role in maintaining peripheral tolerance. At the same time, their functional patterns seem to overlap to a large degree. Therefore, we propose that only the concerted action of a combination of inhibitory receptors is able to maintain peripheral tolerance and prevent autoimmunity.