Nowadays, stent placement has replaced balloon angioplasty as the most commonly performed percutaneous coronary interventional procedure, mainly because of its improved acute and chronic outcome. As a result, however, in-stent restenosis (ISR) has become a widespread problem. The incidence of ISR varies from 10% to 50% and depends on the lesion characteristics and several risk factors, such as small vessel size, longer lesions, and diabetes. Intravascular ultrasound studies have demonstrated that ISR is mainly caused by neointimal proliferation; consequently, this pathologic process has become the target of many preventive and therapeutic approaches. Given the overall disappointment experienced with the use of systemic drug therapies for ISR prevention, stent devices have been coupled with local drug delivery to decrease neointimal proliferation. The results of many published preliminary studies with drug-eluting stents are excellent. However, it is important to remember that the number of treated patients receiving drug-eluting stents has been rather small, the duration of follow-up short, and the lesions treated relatively simple. It is still possible that drug-eluting stents simply delay, rather than eliminate, ISR. Nevertheless, drug-eluting stents remain a very promising therapy for IRS prevention. The results of the ongoing, larger, randomized trials could determine whether the goal of no restenosis can ultimately be achieved. If these studies of drug-eluting stents repeat the same positive results seen in preliminary trials, we can anticipate the advent of a new era in percutaneous intravascular revascularization, possibly reducing restenosis to a problem of the past.