Angiotensin II (Ang II) is the main effector hormone of the renin-angiotensin system (RAS). The pathogenesis of many cardiovascular diseases, including heart failure and hypertension, appear to be related to Ang II production. The generation of Ang II involves angiotensin-converting enzyme (ACE) in circulating and tissue RAS's, as well as non-ACE pathways. ACE and other components of the RAS show natural mutations. In this review, we discuss the molecular genetics of the human RAS in relation to cardiovascular disease, including the clinical effects of known ACE molecular variants and possible pharmacological treatment strategies.