Regulation of sympathoadrenal activity has been a long-time target in the management of hypertension. Regulation of ß-adrenoceptor (ßAR) function has been the most therapeutically important of these targets. The development of effective antihypertensive treatments based on ßAR antagonism paralleled the elucidation of the molecular basis of ß-adrenergic effects by the family of ßARs, which are members of the G-protein-coupled receptor (GPCR) superfamily. ßARs serve as the extracellular face of the transmembrane signalling pathway that results in the consequent activation of heterotrimeric G-proteins and the activation of several other newly appreciated signalling molecules that include ß-arrestins and GPCR kinases (GRKs). The aggregate effect of the activation of these signalling pathways mediates the response to ßAR activation. Paradoxically, the hypertensive state is characterized by impaired ßAR responsiveness. This defect is common to many other receptor systems linked to the stimulator G protein (Gs) and adenylyl cyclase activation. This impairment is principally mediated by receptor-G-protein uncoupling, which has been linked to increased expression and activity of GRK2.