The classical view of biochemical pathways for the formation of biologically active angiotensins continues to undergo significant revision as new data uncovers the existence of important species differences between humans and rodents. The discovery of two novel substrates that, cleaved from angiotensinogen, can lead to direct tissue angiotensin II formation has the potential of radically altering our understanding of how tissues source angiotensin II production and explain the relative lack of efficacy that characterizes the use of angiotensin converting enzyme inhibitors in cardiovascular disease. This review addresses the discovery of angiotensin-(1-12) as an endogenous substrate for the production of biologically active angiotensin peptides by a non-renin dependent mechanism and the revealing role of cardiac chymase as the angiotensin II convertase in the human heart. This new information provides a renewed argument for exploring the role of chymase inhibitors in the correction of cardiac arrhythmias and left ventricular systolic and diastolic dysfunction.