Renin has long been recognized as the preferred, logical target for RAS blockade because it corresponds to the first, highly regulated and rate-limiting step of the system. Initial attempts to inhibit renin were based on diverse strategies, including the use of renin antibodies, peptide analogs of the prosegment of the renin precursor, statin-based peptides, and transition-state synthetic analogs. However, the clinical development of first transition-state synthetic analogs capable of inhibiting renin has faced a number of technical problems. Indeed, the oral administration of these first renin inhibitors in humans did not meet all the necessary criteria (specificity, potency, pharmacokinetic profile, development costs) for these drugs to be considered clinically useful. Molecular modelling and determination of the X-ray crystallographic structure of the active site of renin have led to the identification of new renin inhibitors. The first representative of this class of non-peptide drugs is aliskiren, a potent alkane carboxamide renin inhibitor with a very high binding affinity for renin, resulting in selectivity for this enzyme over other aspartyl proteases. This compound is available in an orally active form and, according to preclinical and clinical investigations, may be of value for treating patients with cardiovascular and renal disorders.