—Since the discovery of nonpeptidic ligands, the receptors for angiotensin (Ang) II have been classified into 2 subtypes (Ang II type 1 receptor [AT₁-R] and Ang II type 2 receptor [AT₂-R]). AT₁-R mediates most of the cardiovascular actions of Ang II. AT₂-R is expressed at very high levels in the developing fetus. Its expression is very low in the cardiovascular system of the adult. The expression of AT₂-R can be modulated by pathological states associated with tissue remodeling or inflammation. In failing hearts or neointima formation after vascular injury, AT₂-R is reexpressed in cells proliferating in interstitial regions or neointima and exerts an inhibitory effect on Ang II-induced mitogen signals or synthesis of extracellular matrix proteins, resulting in attenuation of the tissue remodeling. An extreme form of cell growth inhibition ends in programmed cell death, and this process, which is initiated by the withdrawal of growth factors, is also enhanced by AT₂-R. Cardiac myocyte- or vascular smooth muscle–specific mice that overexpress AT₂-R display an inhibition of Ang II-induced chronotropic or pressor actions, suggesting the role of AT₂-R on the activity of cardiac pacemaker cells and the maintenance of vascular resistance. AT₂-R also activates the kinin/nitric oxide/cGMP system in the cardiovascular and renal systems, resulting in AT₂-R–mediated cardioprotection, vasodilation, and pressure natriuresis. These effects, transmitted by AT₂-R, are mainly exerted by stimulation of protein tyrosine or serine/threonine phosphatases in a Gi protein–dependent manner. The expression level of AT₂-R is much higher in human hearts than in rodent hearts, and the AT₂-R–mediated actions are likely enhanced, especially by clinical application of AT₁-R antagonists. Thus, in this review, the regulation of AT₂-R expression, its cellular localization, its pathological role in cardiovascular and kidney diseases, and pharmacotherapeutic effects of AT₂-R stimulation are discussed.