Mammals and other higher vertebrates have developed an adaptive immune system to defy effectively countless pathogens and cancerous cells encountered during the lifetime of an individual. B and T lymphocytes, which are essential in orchestrating adaptive immune responses, express surface receptors specific for foreign and abnormal self-antigens. Genesis of this antigen receptor repertoire poses significant risks for autoimmunity caused by self-reactive lymphocytes. Therefore, organisms with adaptive immune systems have evolved central and peripheral tolerance mechanisms. In peripheral tissues, regulatory T (T_reg) cells function in a dominant, cell-extrinsic manner to limit inflammatory responses and autoimmune disorders. To tap the potential clinical utility of these specialized lymphocytes, advances have been made in understanding how T_reg cell-mediated suppression of immune effector cells is achieved and regulated. Importantly, signaling induced by a recently identified member of the tumor necrosis factor receptor (TNFR) family, termed glucocorticoid-induced TNFR family-related gene (GITR), abrogates the suppressive effects of T_reg cells. GITR plays a pivotal role in controlling T cell-mediated responses in experimental models of organ-specific autoimmunity, chronic infection, and anti-tumor immunity. These findings highlight the importance of elucidating the molecular underpinnings of GITR-induced signaling. We propose that GITR employs adapter proteins, including TNFR-associated factors (TRAFs), to regulate diverse signaling pathways and transcriptional programs that control the interplay between T_reg cells and immune effector cells.