The classically recognized functions of the renin–angiotensin system are mediated by type 1 (AT₁) angiotensin receptors. Whereas man possesses a single AT₁ receptor, there are two AT₁ receptor isoforms in rodents (AT_1A and AT_1B) that are products of separate genes (Agtr1a and Agtr1b). We have generated mice lacking AT_1B (Agtr1b −/−) and both AT_1A and AT_1B receptors (Agtr1a −/−Agtr1b −/−). Agtr1b −/− mice are healthy, without an abnormal phenotype. In contrast, Agtr1a −/−Agtr1b −/− mice have diminished growth, vascular thickening within the kidney, and atrophy of the inner renal medulla. This phenotype is virtually identical to that seen in angiotensinogen-deficient (Agt−/−) and angiotensin-converting enzyme-deficient (Ace −/−) mice that are unable to synthesize angiotensin II. Agtr1a −/−Agtr1b −/− mice have no systemic pressor response to infusions of angiotensin II, but they respond normally to another vasoconstrictor, epinephrine. Blood pressure is reduced substantially in the Agtr1a −/− Agtr1b −/− mice and following administration of an angiotensin converting enzyme inhibitor, their blood pressure increases paradoxically. We suggest that this is a result of interruption of AT₂-receptor signaling. In summary, our studies suggest that both AT₁ receptors promote somatic growth and maintenance of normal kidney structure. The absence of either of the AT₁ receptor isoforms alone can be compensated in varying degrees by the other isoform. These studies reaffirm and extend the importance of AT₁ receptors to mediate physiological functions of the renin–angiotensin system.