Several different strategies have been followed to block the activity of renin, the enzyme catalysing the first and rate-limiting step in the renin-angiotensin cascade. The unique substrate specificity of this enzyme makes it an attractive target for specifically interfering with the renin-angiotensin system. Attempts to block the activity of renin in animals by an immunological approach, with either active or passive immunization against renin, have been successful. This approach has not been considered as a realistic therapy in humans for the treatment of hypertension or heart failure, but has provided useful tools for purifying and quantifying renin. Considerable efforts have been focused on the design of orally active, synthetic inhibitors of renin. This has resulted in the discovery of low molecular weight pseudo-tetrapeptide compounds that are resistant to enzymatic cleavage and are potent and selective inhibitors of renin. Studies in animal models and preliminary studies in humans indicate that renin inhibitors have the same therapeutic potential as angiotensin-converting enzyme inhibitors. However, the generally poor oral bioavailability and rapid elimination of currently available renin inhibitors have prevented their development as useful drugs. Inhibitors with better oral bioavailability and a long duration of action are needed to assess their full therapeutic potential and to determine whether they offer advantages over the angiotensin-converting enzyme inhibitors or the more recently developed angiotensin II-receptor antagonists.