Summary: Signaling through the interleukin-2 receptor (IL-2R) contributes to T-cell tolerance by controlling three important aspects of regulatory T-cell (Treg) biology. IL-2 is essential for thymic Treg development and regulates Treg homeostasis and suppressive function. Analogous to activated conventional T lymphocytes, IL-2R signaling also plays an important part in Treg cell growth, survival, and effector differentiation. However, Treg cells somewhat distinctively assimilate IL-2R signaling. In particular, Treg cells require essentially only IL-2-dependent receptor proximal signal transducer and activator of transcription 5 (Stat5) activation, as they contain inhibitory pathways to minimize IL-2R-dependent activation of the phosphatidyinositol 3-kinase/Akt pathway. Moreover, many IL-2R-dependent activities, including full induction of Foxp3 expression, in Treg cells require minimal and transient Stat5 activation. Thus, Treg cells are equipped to sense and then develop and function within biological niches containing minimal IL-2. These distinguishing features of IL-2R signaling provide a mechanistic underpinning for using IL-2 as an agent to selectively target Treg cells in immunotherapy to induce tolerance in autoimmune diseases and in allogeneic transplant recipients.