In this paper, we review the hypothesis that activated tissue renin-angiotensin systems play a detrimental role in heart failure. The main arguments for this idea are discussed: a) tissue renin-angiotensin systems behave functionally distinct from the circulating renin-angiotensin system; b) tissue renin-angiotensin systems are activated in heart failure; c) activated tissue renin-angiotensin systems induce cardiovascular dysfunction. Finally, this hypothesis predicts that optimal treatment in heart failure requires the inhibition of tissue renin-angiotensin systems. However, studies pertaining to this prediction are still lacking, particularly in human subjects.