The family of G protein–coupled receptors (GPCRs) responds selectively to ligands ranging from hormones to odorants and from neurotransmitters to photons. Following engagement of the ligand, these serpentine receptors selectively activate heterotrimeric G proteins that in turn transmit signals to distal effector pathways. The role of GPCRs in hypertension and cardiovascular diseases is well established (1). For example, pharmacological antagonists of GPCRs, such as the β-adrenergic and angiotensin receptors, are cornerstones of therapy in the treatment of hypertension and its complications. GPCR signaling is triggered by ligand-induced conformational changes in intracellular portions of the receptor that promote exchange of guanosine 5′-diphosphate (GDP) for guanosine 5′-triphosphate (GTP) on the Gα subunit of the heterotrimeric G protein. This is followed by dissociation of the GTP-bound Gα from the Gβγ dimer (Figure ​(Figure1).1). The dissociated subunits can then interact with effector molecules to propagate the intracellular signal. The duration and intensity of signaling are further regulated by GTPase-activating proteins (GAPs). GAPs accelerate the hydrolysis of Gα-bound GTP, returning the Gα subunit to its inactive form. The regulators of G protein signaling (RGSs) are a family of proteins with GAP activity. To date, more than 20 RGS proteins have been identified. These proteins are characterized by the presence of canonical RGS domains that exhibit G protein–GAP activity (2). Although physiological functions for most of the RGS family members have not been identified, recent studies have assigned roles to some RGS proteins. For example, RGS9-1 controls photosensitization in the eye (3). The RGS protein Sst2 mediates feedback inhibition of mating pheromone responses in yeast (4, 5). In this issue of the JCI, Heximer and associates describe a novel function of another RGS family member, RGS2, in regulation of blood pressure and vascular structure (6). Figure 1 Regulation of G protein signaling by RGS2. (a) During basal state the AT1 receptor spans the cell membrane and is associated with a heterotrimeric G protein. (b) Binding of hormone (angiotensin II) activates the G protein–coupled AT1 receptor, ...