Coronary artery disease is a leading cause of morbidity and mortality in the United States and across the world. The economic impact of coronary artery disease is staggering and on the rise. Percutaneous transluminal coronary angioplasty is widely used to treat severe, symptomatic coronary stenosis. The Achilles heel of angioplasty is restenosis of those treated arteries. As a result, numerous therapies, including mechanical and pharmacological approaches, to prevent restenosis have been studied. A greater understanding of the pathophysiology of restenosis has enhanced the success of these therapeutic approaches. To date, the most important and successful approach to limit restenosis has been the use of coronary stents. Stents have reduced the rate of restenosis from approximately 50% down to 20-30%. However, in-stent restenosis presents a new and an even more challenging dilemma. The success of adjunctive drug therapy has been promising, but, as of yet, very limited. Antithrombotic agents have reduced acute thrombosis and many of the acute complications of angioplasty. New approaches and therapies are very encouraging, and provide great hope in the treatment of restenosis. Brachytherapy has shown success in the treatment of in-stent restenosis, and recently has been approved by the United States Food and Drug Administration for this indication. Drug-eluting stents using antiproliferative drugs are the most exciting new advance in preventing restenosis, currently in Phase III trials. Gene therapy, targeted drug delivery, and newer antithrombotic agents are also under investigation. We will review the pathophysiology of restenosis, animal models, pharmacological therapies, and mechanical approaches for the treatment of restenosis.