An imbalance between the classical and alternative renin-angiotensin system (RAS) is a characteristic feature of the multifactorial pathophysiology responsible for vasodilatory shock and provides a rationale for its treatment with exogenous angiotensin II (AngII). A reduction in pulmonary vascular endothelial angiotensin converting enzyme (ACE) activity (septic shock) or lack of exposure to the enzyme (vasoplegia after cardiopulmonary bypass) combine with an intense pro-inflammatory state to decrease AngII formation, allow further renin release, and increase production of angiotensin I and its vasodilatory metabolic products including Ang-(1-7). Other factors including blockade of ACE-mediated bradykinin degradation, enhanced dipeptidyl peptidase-3 metabolism of AngII, and downregulation of the angiotensin II type 1 receptor contribute further to vasodilatory shock. This article has the following objectives: 1) briefly review the physiology of the normal RAS; 2) describe alternative RAS metabolism and its role in the pathophysiology of septic shock; 3) summarize the current support for AngII in this setting; 4) distinguish the differences and note the similarities between septic shock and vasoplegia after CPB; 5) discuss the evidence for the use of AngII for the treatment of vasoplegia; 6) examine the role of AngII therapy in vasodilatory shock associated with mechanical circulatory support and ventricular assist devices; 7) comment on the potential use of AngII as a treatment for vasodilation in patients undergoing liver transplantation; and lastly, 8) identify questions that remain to be addressed about the benefits and limitations of AngII in various vasodilatory shock phenotypes.