Interleukin-2 (IL-2) promotes both tolerance (by supporting regulatory T cell (Treg) development and homeostasis) and immunity (by promoting T effector and memory responses). These dual activities raise the concern that IL-2-based immunotherapy will target both Treg and Teffector/memory (TEM) cells. Recent clinical studies, however, suggest that an appropriate low-dose of IL-2 may promote tolerance over immunity by selective activation of Tregs. We have evaluated the mechanisms that favor activation of Tregs by low-dose IL-2. Dose-response studies measuring IL-2-dependent activation of pSTAT5 revealed that Tregs from normal individuals were 5-15-fold more responsive to IL-2 than TEM cells. Higher levels of IL-2Rα and γc on Tregs and other intrinsic mechanisms partially account for their enhanced IL-2R signaling. Genome-wide profiling identified 388 mRNAs that were IL-2-dependent (1.5-fold) in human Tregs. Importantly, when IL-2-dependent activation of selected targeted were compared in Treg and TEM cells by qPCR, most targets in Tregs were substantially activated (>75% maximal levels) at a 100-fold lower concentration of IL-2. Our findings indicate that low levels of IL-2 selectively activate Tregs to broadly induce their IL-2 gene program. These findings provide a rationale for the use of low-dose IL-2 as a therapy to selectively boost Tregs and immune tolerance in clinical setting to suppress unwanted immune responses.