Regulators of G protein signaling (RGS) proteins accelerate the GTPase activity of Gα protein subunitsin vitro, negatively regulating G protein-coupled receptor signaling. The physiological role of mammalian RGS proteins is largely unknown. The RGS family memberrgs2was cloned as an immediate early response gene up-regulated in T lymphocytes after activation. To investigate the role of RGS2in vivo, we generatedrgs2-deficient mice. We show that targeted mutation ofrgs2in mice leads to reduced T cell proliferation and IL-2 production, which translates in an impaired antiviral immunityin vivo. Interestingly,rgs2−/−mice also display increased anxiety responses and decreased male aggression in the absence of cognitive or motor deficits. RGS2 also controls synaptic development and basal electrical activity in hippocampal CA1 neurons. Thus, RGS2 plays an important role in T cell activation, synapse development in the hippocampus, and emotive behaviors.