RGS proteins attenuate the activities of heterotrimeric G proteins largely by promoting the hydrolysis of the activating nucleotide GTP. This review discusses the interactions of RGS proteins and G proteins and how those interactions are regulated by a variety of factors including auxiliary proteins and other cellular constituents, posttranslational modifications, and intracellular localization patterns. In addition, we discuss progress that has been made toward understanding the roles that RGS proteins play in vivo, and how they may serve to govern responses to G protein-coupled receptors upon acute and prolonged activation by agonists.