Percutaneous transluminal coronary angioplasty (PTCA) was introduced 22 years ago as a nonsurgical catheter-based treatment for obstructive coronary artery disease. Over the following 2 decades, major advances in equipment and techniques led to tremendous growth in the use of PTCA to treat coronary artery disease and angina. Restenosis persists as the limiting factor in the maintenance of vessel patency after PTCA, occurring in 30% to 50% of patients and accounting for significant morbidity and health care expenditures. Plaque persistence and vessel recoil, thrombus formation, constrictive remodeling, and neointimal proliferation are the primary contributors to the development of restenosis after PTCA. Early clinical trials in restenosis prevention using various revascularization devices, antiplatelet drugs, antithrombotic drugs, and antiinflammatory drugs were uniformly negative. Coronary stents are the only devices that have shown a reduction in the incidence of restenosis. Recently, novel therapies, such as intracoronary radiation, antioxidant drugs, and platelet-derived growth factor antagonists, have shown reductions in the incidence of restenosis in small randomized trials. This review focuses on the etiology and pathophysiology of restenosis and discusses current and future therapies that may reduce the incidence of restenosis.