Small interfering RNAs (siRNA) have emerged as important new therapeutics that can knock down previously undruggable targets in an efficient and long-lasting manner. Initially exploited for rare diseases, licensing of inclisiran in hypercholesterolemia positions them as viable approaches in common conditions. Zilebesiran is an siRNA that knocks down angiotensinogen (AGT) in the liver, the sole precursor of angiotensin peptides. It has now completed phase I studies. Patients with hypertension were randomly assigned in a 2:1 ratio (n=12/dose) to receive either a single ascending sc dose of zilebesiran (10, 25, 50, 100, 200, 400 or 800mg) or placebo and followed for 24 weeks (Part A). Phase I also assessed the effect of 800mg on BP under low- or high-salt diet (Part B), and when given with irbesartan (Part C). Endpoints included safety, PK & PD, and change from baseline in ambulatory systolic (SBP) and diastolic BP (DBP) measured over 24-h. Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no significant reports of hypotension, hyperkalemia, or worsened renal function. In Part A, zilebesiran decreased serum AGT dose-dependently. Single doses (≥200 mg) were associated with decreased SBP (>10 mm Hg) and DBP (>5 mm Hg) by week 8. These changes were consistent throughout the diurnal cycle and sustained at 24 weeks. Results from Parts B and C were consistent with modulation of BP: attenuated by a high-salt diet; augmented by irbesartan. Based on impressive efficacy, and acceptable safety, phase II studies are underway (KARDIA I examines dose and dosing interval; KARDIA 2 explores combination with other agents). Safety data in larger cohorts, with broader co-morbidities are needed, but targeting AGT seems a powerful way to inhibit the renin-angiotensin system and may have potential beyond hypertension, such as in chronic heart and kidney disease. The long action of zilebesiran may potentially be beneficial for adherence and BP stability.