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.