The treatment of in-stent restenosis (ISR) remains one of the major therapeutic challenge for the interventional cardiologist. All percutaneous mechanical approaches have shown disappointing results and the recurrence of ISR was reported to be unacceptably high. Currently, the only proven effective therapy available for the treatment of ISR, at least for the most complex lesions, is vascular brachytherapy. However, this therapy is limited by potential side effects and logistic requirements. The introduction of drug-eluting stents, that carry and release antiproliferative agents, have demonstrated to virtually eliminate ISR in de novo lesions. In the light of this promising results for de novo lesions, sirolimus-eluting stents (SES) were recently used for the treatment of ISR in 2 pilot studies. In Sao Paulo, 25 patients with ISR treated with SES (1.4 stent per lesion) presented 4% ISR and no clinical events at 1 year. In Rotterdam, 16 patients with severe ISR were treated with 26 SES. Intravascular ultrasound evaluation demonstrated successful inhibition of neointimal hyperplasia with 1.1% volume obstruction of the stent, which is similar to the Sao Paulo series (0.8%). At 9 months clinical follow-up, 3 patients had experienced 4 major adverse cardiac events (2 deaths and 1 acute myocardial infarction necessitating repeat target vessel angioplasty). With the results presently available, SES implantation can be considered safe and potentially efficacious in the treatment of ISR. However, multicenter, long-term randomized studies are warranted in order to evaluate this new treatment concept.