The development of cardiovascular diseases, such as heart failure, cardiac enlargement, high blood pressure, and atherosclerosis, can be attributed to abnormal activation of the renin-angiotensin-aldosterone system (RAAS) pathway. Even though a large number of important RAAS enzymes and peptide hormones have been studied extensively, the relevance of angiotensinogen, which is the precursor substrate of the RAAS pathway, is not yet fully understood. Research on single nucleotide polymorphisms (SNPs) of angiotensinogen has led to a better understanding of the links between angiotensinogen and hypertension, congestive heart failure and atherosclerotic cardiovascular disease. Patients who suffer from heart failure, myocardial infarction and hypertension have shown significant improvements in their clinical outcomes with targeted pharmaceutical therapy for RAAS. However, all of these drugs block RAAS components downstream of angiotensinogen and stimulate compensatory mechanisms, which limits the therapeutic efficacy of these treatments when used alone as monotherapy. Upstream targeting of the RAAS with an angiotensinogen inhibitor has the potential to be more effective in patients with weak RAAS inhibition and has a better safety profile than multi-agent blockade of the RAAS. These newly developed treatments that target angiotensinogen through antisense oligonucleotides or silencing RNA technologies offer a unique perspective on the pathobiology of angiotensinogen. These treatments also show promise as the next frontier in the treatment of cardiovascular disease.