Classically, the CD28/cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and B7 families of cell surface molecules regulate complex signaling pathways that profoundly affect T‐cell responses. The recent identification and characterization of additional CD28 and B7 family members including programmed death‐1 (PD‐1), programmed death ligand‐1 (PD‐L1) (B7‐H1), and PD‐L2 (B7‐DC) has added to the complexity and greater appreciation of how surface molecules control T‐cell activation and peripheral tolerance. CD28/B7 interactions mediate co‐stimulation and significantly enhance peripheral T‐cell responses. CTLA‐4, in contrast, interacting with the same B7 molecules, results in decreased T‐lymphocyte activity and regulates the immune response. Similarly, PD‐1 interactions with PD‐L1 and PD‐L2 downmodulate T‐cell immune responses. Despite these similarities, the regulatory roles of the CTLA‐4 and PD‐1 pathways are distinct. This may be due, at least in part, to the differential expression patterns of the CTLA‐4 and PD‐1 ligands both temporally and spatially. This article examines the role of CTLA‐4 and PD‐1 in limiting autoreactivity and establishing peripheral self‐tolerance with the hypothesis that CTLA‐4 signals are required early in the lymph node during initiation of an immune response and PD‐1 pathways act late at the tissue sites to limit T‐cell activity.