The occurrence of in-stent restenosis is a major drawback of percutaneous transluminal coronary angioplasty with stent placement. Target vessel revascularization is necessary in 15% of patients who receive a stent. Recent advances in the development of drug-eluting stents have reduced these numbers tremendously. However refinement of antirestenotic therapies remains obligatory. The emerging interest in more physiological antirestenotic therapies might unchain an interest in the well-known inhibitors of the rennin-angiotensin system (RAS), the angiotensin-converting enzyme inhibitors, and the angiotensin II type I receptor blockers. Contradictory results overshadow the discussion of whether intervention in the RAS could prevent in-stent restenosis. This review discusses the pathophysiology of in-stent restenosis, the role of the RAS in in-stent restenosis, and the possible role of RAS intervention in the prevention of in-stent restenosis.