G protein-coupled receptors (GPCRs) are expressed ubiquitously and involved in a variety of physiologic and pathologic processes. One of the key steps in the GPCR signaling cascade is the phosphorylation of the Galpha-subunit that triggers its dissociation from the Gbetagamma-subunit and from the receptor, allowing both G protein subunits to activate different downstream second messengers. Thereafter, Galpha hydrolyzes the attached guanosine triphosphate (GTP) to guanosine diphosphate (GDP) by its inherent enzymatic activity and terminates signaling. Small/connecting proteins that act as GTPase activating proteins (GAP) accelerate this process. Regulator of G protein signaling (RGS) proteins play a key role in the regulation of GPCRs, by acting as GAP and increasing the rate of GPCRs deactivation. RGS2 affects GPCR-dependent and GPCR-independent pathways. RGS2 -/- displayed an increase of blood pressure (BP) mainly by an increase of total peripheral resistance. After N(omega)-nitro-L-arginine methyl ester (L-NAME) RGS2 -/- mice responded with a smaller BP increase during the day than RGS2 +/+, suggesting an impaired NO signaling. Infusion of angiotensin II increased BP stronger in RGS2 -/- compared with RGS2 +/+. In summary, GPCR-dependent and GPCR-independent pathways are involved in BP changes of RGS2 -/- mice. Interactions between GPCRs and RGS2 represent a regulatory mechanism for fine-tuning of BP which may be important for hypertension and may be considered as a potentially novel drug target.