Use of drugs that inhibit the renin-angiotensin system is an effective way to intervene in the pathogenesis of cardiovascular and renal disorders. The idea of blocking the renin system at its origin by inhibition of renin has existed for more than 30 years. Renin inhibition suppresses the generation of the active peptide angiotensin II. The first generation of orally active renin inhibitors were never used clinically because of low bioavailability and weak blood-pressure-lowering activity. At present, aliskiren is the first non-peptide orally active renin inhibitor to progress to phase-III clinical trials. It might become the first renin inhibitor with indications for the treatment of hypertension and cardiovascular and renal disorders. Novel compounds with improved oral bioavailability, specificity, and efficacy are now in preclinical development. This Review summarises the development of oral renin inhibitors and their pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren.