Bare metal stents (BMS) successfully prevented abrupt artery closure and reduced the restenosis rate compared with balloon angioplasty. This review summarizes laboratory and recent clinical investigations concerning neointimal formation and endothelial regeneration after vascular injury. BMS efficacy was severely hampered by proliferating vascular smooth muscle cells (VSMCs), and the resultant neointimal hyperplasia, which is the only mechanism responsible for restenosis after metal stent placement. The advent of drug-eluting stents (DES) in 2002 have since then revolutionized interventional cardiology. By using the stent struts as a platform coated with polymers to elute drugs targeting VSMC proliferation, a substantial attenuation of in-stent restenosis is feasible. As with any medical innovation this technology still has restrictive factors, and novel approaches are promoted to improve the safety and efficacy of DES. Indeed, the antiproliferative properties of DES impair and/or delay endothelialization, hence leading to late stent thrombosis. Improvements in percutaneous coronary intervention procedures include the use of the so-called "second-generation DES", together with new coating technologies, bioabsorbable stents, and non-drug-based stent coatings. Particular emphasis will be placed on the concept that endothelial regeneration might be pursued as well as reduction of VSMC proliferation to allow stable successful revascularization after DES deployment.