T lymphocytes play a key role in immunity by distinguishing self from nonself peptide antigens and regulating both the cellular and humoral arms of the immune system. Acquired, antigen‐specific unresponsiveness is an important mechanism by which T cell responses to antigen are regulated in vivo. Clonal anergy is the term that describes T cell unresponsiveness at the cellular level. Anergic T cells do not proliferate or secrete interleukin (IL)‐2 in response to appropriate antigenic stimulation. However, anergic T cells express the IL‐2 receptor, and anergy can be broken by exogenous IL‐2. Anergy can be induced by submitogenic exposure to peptide antigen in the absence of a costimulatory signal provided by soluble cytokines or by interactions between costimulatory receptors on T cells and counter‐receptors on antigen‐presenting cells. The molecular events that mediate the induction and maintenance of T cell anergy are the focus of this review. The molecular consequences of CD28–B7 interaction are discussed as a model for the costimulatory signal that leads to T cell activation rather than the induction of anergy.