The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and body fluid homeostasis and is a mainstay for the treatment of cardiovascular and renal diseases. Angiotensin II and aldosterone are the two most powerful biologically active products of the RAAS, inducing all of the classical actions of the RAAS including vasoconstriction, sodium retention, tissue remodeling and pro-inflammatory and pro-fibrotic effects. In recent years, new components of the RAAS have been discovered beyond the classical pathway that have led to the identification of depressor or so-called protective RAAS pathways and the development of novel therapies targeting this system. Moreover, dual inhibitors which block the RAAS and other systems involved in the regulation of blood pressure or targeting upstream of angiotensin II by selectively deleting liver-derived angiotensinogen, the precursor to all angiotensins, may provide superior treatment for cardiovascular and renal diseases and revolutionize RAAS-targeting therapy. •RAAS plays key roles in cardio-metabolic health and disease.•Classical inhibitors block angiotensin I and II generation or downstream effects.•Latest form of RAAS inhibitor is combination of an ARB with NEP inhibitor (ARNI).•RAAS agonists target the depressor or so called protective RAAS pathways.•Deletion of liver-derived angiotensinogen may revolutionize RAAS inhibition.