Despite significant advances in technology and technique, coronary restenosis remains the primary limitation of percutaneous transluminal coronary angioplasty (PTCA). Among patients undergoing PTCA, between 20% and 50% of patients who do not receive a stent and 10%-30% of those who do receive a stent develop restenosis within 6 months of the procedure. Drug-eluting stents, which release high local concentrations of antiproliferative or immunosuppressive agents directly into the vessel wall at the site of the lesion, have dramatically reduced the incidence of restenosis in patients undergoing PTCA. However, even with drug-eluting stents, a significant percentage of higher-risk patients develop in-stent restenosis. These data suggest that a role remains for effective, well-tolerated systemic pharmacologic therapies to further reduce the rate of restenosis. To date, the majority of systemic agents tested for restenosis prevention have failed to show significant benefit. Only 2 agents, probucol and cilostazol, have consistently demonstrated efficacy in preventing restenosis. In addition, the investigational agent AGI-1067 has demonstrated promising efficacy in early clinical trials. Together with drug-eluting stents, these therapies may for the first time reduce the rate of restenosis to near zero, even in high-risk patients, such as individuals with diabetes mellitus.