The history of the renin angiotensin system (RAS) traces its roots to the seminal experiments of Tigerstedt and Bergman describing a pressor response in the rabbit following injection of a rabbit kidney homogenate. These studies were the first to describe the hypertensive effect of renin and laid the foundation for future investigations into the RAS pathway. Several crucial studies followed over the next 50 years that further elaborated additional key components of the RAS, including the identification of angiotensin II (AngII) as the principal substance mediating the activity of this system. Skeggs went on to explain how therapeutic benefit could be achieved by interfering with this system at several distinct points: by blocking the receptor for AngII, by inhibiting angiotensin converting enzyme (ACE) as the enzymatic step required for generation of AngII, or by preventing the formation of AngI through direct inhibition of renin. Interestingly, these investigators realized early on that 'Since renin is the initial and rate-limiting substance in the renin-hypertensin system, it would seem that this last approach would be the most likely to succeed.' It has been shown consistently that blockade of the RAS, either with an ACE inhibitor (ACEi) or with an AngII AT1 receptor blocker (ARB) reduces blood pressure (BP). However, a powerful counter-regulatory mechanism is activated during RAS blockade and is in part responsible for the 'flat' dose-response relationship observed with the use of these inhibitors. Under normal physiologic conditions, AngII inhibits renin release through stimulation of the AT1 receptor. Therapeutic interventions that either reduce AngII (ACEi) or attenuate AT1 signaling (ARB) ultimately result in enhanced release of renin. Consequently, the historical depiction of this system as a linear cascade is an inappropriate representation of the pathway. The RAS is now better portrayed as a physiological circuit encompassing a negative feedback 'loop' whereby renin levels are controlled by the amount of AngII present in plasma and tissues. This renders renin a highly attractive target from a therapeutic standpoint, as it would provide the only tactic to reduce plasma renin activity and thus offers a novel approach for the management of hypertension. While a compensatory rise in renin occurs as a result of RAS blockade with an ACEi, ARB, or a renin inhibitor, renin is rendered ineffective only by renin inhibition. Renin inhibitors bind to the active site of renin, a member of the aspartic protease family with high specificity for its endogenous substrate angiotensinogen, and are now commonly referred to as 'direct renin inhibitors' (DRI), as opposed to drugs interfering with other components of the RAS, like ACE inhibitors, ARBs, or β-adrenoceptor antagonists. Despite many treatment options available to the clinician, hypertension remains an important public health issue. Hypertension affected more than 65 million Americans and more than 25% of adults worldwide and is a key risk factor for myocardial infarction, stroke, and heart and renal failure. Its prevalence is expected to increase by 60% to >1.5 billion people worldwide by 2025. Academic institutions and major pharmaceutical companies have committed substantial resources over the past 50 years in an effort to discover the best therapeutic tactic for modulating the RAS. Initial therapeutic success was achieved with the introduction of ACEi and then with the identification of ARBs a decade later. While it was widely recognized that direct renin inhibition held great therapeutic potential, the design of small nonpeptidic molecules that effectively interact with the catalytic domain of renin and that demonstrate oral efficacy in humans remained elusive for more than 2 decades. Compound 1 (aliskiren, CGP60536B, SPP100) represents a new generation of orally highly effective DRIs of a unique structural class designed by molecular modeling and X-ray crystallography. This drug was introduced in the United States as Tekturna and in Europe as Rasilez in 2007 and hence became the first new therapy for the treatment of hypertension in more than 10 years. Since the late 1990s, a resurgence of interest in DRIs in the industry became increasingly evident and was driven by several major advancements. Emerging new insights at the molecular level related to human renin-inhibitor active site interactions have paved new avenues for designing distinct chemotype inhibitors. The introduction of transgenic rodent models provided the capability to assess biological actions in small animals and thus reduced reliance on the use of nonhuman primates. Also, the advanced clinical testing of 1 offered promise that this long sought after therapeutic approach might finally become a reality. Most importantly, extensive clinical trial results are now available and demonstrate its benefit. Previous DRIs had been evaluated in limited clinical testing with short-term administration. The objective of this review is to highlight key events and recent advances in the evolution of non-peptide peptidomimetic DRIs. Special emphasis will be placed on the successful structure-based strategies that enabled the discovery of several novel classes of DRIs. The potential limitations associated with these inhibitors and opportunities for future directions of renin inhibitor design will be discussed from a chemical and biological perspective. Lessons learned will also be discussed in an effort to provide a unique perspective on the development of 1. With its introduction, it is now very important to distinguish this mechanism of action from indirect means of inhibiting renin. In this regard, ongoing clinical trials designed to demonstrate a clear benefit, beyond an effect on blood pressure, by reduction in morbidity and mortality are of paramount importance.