T cell migration toward sites of antigen exposure is mediated by G protein signaling and is a key function in the development of immune responses. Regulators of G protein signaling (RGS) proteins modulate G protein signaling; however, their role in the regulation of adaptive immune responses has not been thoroughly explored. Herein we demonstrated abundant expression of the Gi/Gq-specific RGS3 in activated T cells, and that diminished RGS3 expression in a T cell thymoma increased cytokine-induced migration. To examine the role of endogenous RGS3 in vivo, mice deficient in the RGS-domain (RGS3^RGS ) were generated and tested in an experimental model of asthma. Compared to littermate controls, the inflammation in the RGS3^RGS mice was characterized by increased T cell numbers and the striking development of perivascular lymphoid-structures. Surprisingly, while innate inflammatory cells were also increased in the lungs of RGS3^RGS mice, eosinophil numbers and Th2 cytokine production was equivalent to control mice. In contrast, T cell numbers in the draining lymph nodes (dLN) were reduced in the RGS3^RGS demonstrating a redistribution of T cells from the dLN to the lungs via increased RGS3^RGS T cell migration. Together these novel findings show a non-redundant role for endogenous RGS3 in controlling T cell migration in vitro and in an in vivo model of inflammation.