Chronic autoimmune disease in humans is the result of a failure to control autoreactive immune cells in the periphery. This control is largely achieved by inhibition of newly activated and memory cells. A number of negative immune regulatory pathways have been characterized. The cell surface coreceptor cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) has emerged as a critical attenuator of T‐cell activation and an essential component of the regulatory systems that serve to maintain peripheral tolerance. CTLA‐4 expression is induced on the surface of T cells after they have received a costimulatory signal from antigen‐presenting cells (APCs) via engagement of CD28 on the T‐cell surface. CTLA‐4 attenuates this costimulation by competing for CD28 ligands and through direct effects on APCs via the same ligands utilized by CD28. A large number of genetic association studies suggest that the CTLA‐4 gene is a locus of susceptibility to autoimmune disease. However, specific functional defects in the CTLA‐4 gene in patients have not been identified to date. Elucidating the role of CTLA‐4 in immune tolerance has also led to a number of therapeutic applications, particularly in the treatment of malignancy and autoimmune disease.