In mild to severe heart failure, activation of the renin-angiotensin-aldosterone system is the primary abnormality. Increasing plasma levels of renin, angiotensin and aldosterone have direct effects on myocardium but also sodium and water handling, vascular contractility and reverse remodeling. Medical therapy to inhibit the renin-angiotensin-aldosterone system is the cornerstone of treatment for cardiomyopathy and heart failure. This chapter will examine this neurohormonal pathway and discuss the deleterious effects when activated. Current medical therapy, aimed to block activation points along the pathway, will be reviewed.