The introduction of percutaneous transluminal coronary angioplasty has revolutionized the field of cardiology by providing patients with coronary artery disease immediate and effective therapy. Overshadowing the early success of angioplasty was the high rate of angiographic restenosis and recurrent symptoms at 6 months. The use of stents reduced the incidence of restenosis; however, the rise in the number of patients undergoing percutaneous interventions produced a new problem of restenosis occurring within the stent: in-stent restenosis (ISR). Mechanical approaches, including directional and rotational atherectomy and systemic pharmacotherapy, have failed to demonstrate a reduction in ISR in randomized clinical trials. Intravascular brachytherapy is currently the only approved therapy for ISR, although this treatment has numerous unresolved questions and is not effective in a large percent of patients. Drug-eluting stents have reduced the incidence of restenosis by providing localized therapy to the targeted lesion without systemic toxicity. The purpose of this review is to synthesize data from major clinical trials involving the 2 most successful agents used in the prevention of restenosis: sirolimus and paclitaxel. The cellular and molecular mechanisms of both ISR and restenosis postangioplasty derived from animal models will be introduced. Second, an overview of 3 alternate interventions that attempt to reduce the rates of restenosis is presented. Finally, the major randomized, controlled trials involving sirolimus and paclitaxel are described, and their clinical implications and use as a possible solution in the prevention of restenosis is discussed.