All forms of percutaneous coronary intervention confer injury on the vessel. The arterial response to that injury is the basis for long-term outcome. The stent prevents remodeling but enhances neointimal formation, and it is this neointima that is principally responsible for in-stent restenosis. Neointima forms in response to thrombus, inflammation, intimal and medial dissections, and elastic recoil of the arterial wall when a stent is not placed. Current efforts to solve restenosis center on limiting neointimal hyperplasia through drug-eluting stents and vascular brachytherapy. This article reviews arterial injury during revascularization in both patients and animal models and discusses the nature and formation of neointimal hyperplasia.