The development of cardiovascular diseases, such as heart failure, cardiac hypertrophy, high blood pressure, and atherosclerosis, can be attributed to the abnormal activation of the renin-angiotensin-aldosterone system (RAAS) pathway. Even though a great number of important RAAS enzymes and peptide hormones have been investigated in depth, the relevance of angiotensinogen, which is the precursor substrate of the RAAS pathway, is still not completely known. The research of angiotensinogen single-nucleotide polymorphisms (SNPs) has provided insight into connections 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 due to targeted pharmaceutical therapy for RAAS. However, all of these medicines block RAAS components that are downstream of angiotensinogen and stimulate compensatory mechanisms, which limits the therapeutic effectiveness of these treatments when used alone as monotherapy. Upstream RAAS targeting by an angiotensinogen inhibitor has the potential to be more successful in patients with poor RAAS inhibition and has a better safety profile than multiagent RAAS blocking. These newly developed treatments that target angiotensinogen through antisense oligonucleotides or silencer RNA technologies provide a unique perspective into the pathobiology of angiotensinogen. These treatments also show promise as the next frontier in treating cardiovascular disease.