Summary: CD4+ T cells are the master regulators of adaptive immune responses, and many autoimmune diseases arise due to a breakdown of self‐tolerance in CD4+ T cells. Activation of CD4+ T cells is regulated by not only the binding of peptide‐major histocompatibility complexes to T‐cell receptor but also costimulatory signals from antigen‐presenting cells. Recently, there has been progress in understanding the extracellular and intracellular mechanisms that are required for implementation and maintenance of T‐cell tolerance. Understanding of the molecular mechanisms underlying T‐cell tolerance will lead to development of pharmacological approaches either to promote the tolerance state in terms of autoimmunity or to break tolerance in cancer.