Hypertension is the most common cardiovascular disease. The regulator of G-protein signalling (RGS) proteins modify the activity of G proteins, and mice deficient in RGS-2 are hypertensive. On vascular smooth muscle, RGS-2 is involved in cross-talk between the nitric oxide (NO)-relaxation pathway and thrombin-contraction pathway. RGS-2 binds to the cGMP-dependent protein kinase I-alpha from the NO relaxation pathway to terminate protease-activated receptor-1 signalling. It has been suggested that RGS-2 is a new drug development target for hypertension. Mice deficient in RGS-2 also have impaired antiviral immunity. It is difficult to envisage how RGS-2 could be targeted to have effects on the cardiovascular system without affecting immunity. Also, it is not clear whether or not targeting RGS-2 will have advantages over targeting receptors. Only an increased understanding of the physiological and pathological role of RGS-2 will help us resolve these issues.