The migration of B lymphocytes into distinct microenvironments in secondary lymphoid tissues and maintenance of cells in these micro-domains is strictly structured and likely supports the proper regulation of immune responses to both foreign and self-antigens. Chemokines 'and other chemoattactants 'signals serve as signposts to direct cell migration. They signal cells through heptahelical receptors, which couple to heterotrimeric G proteins (G protein-coupled receptors or GPCRs).The regulation of the signals transduced through these receptors ultimately determines the positioning of cells in lymphoid tissues. A variety of mechanisms regulate GPCR signaling including a family of approximately 25 proteins termed regulators of G protein signaling (RGS).These proteins act as GTPase activating proteins for G alfa subunits and can also function as effector antagonists of specific G alfa subunits, thereby attenuating signaling through GPCRs such as chemokine receptors. RGS proteins possess some degree of receptor and G alfa subunit specificity. Thus, the particular spectrum of RGS proteins and their expression levels within a cell will determine the duration and magnitude of G protein signaling initiated by chemokines. In this review we illustrate the role RGS proteins have in regulating B cell signaling responses to chemoattractant stimuli during homeostasis as well as during an immune response.