Stent implantation represents the most commonly performed percutaneous coronary intervention nowadays. However, instent restenosis due to exaggerated neointimal hyperplasia remains a problem to overcome. Neointimal hyperplasia is a vascular response to stent injury; it mainly consists of smooth muscle cells proliferation. The underlying molecular mechanisms of restenosis were explained in this review article. Recently, drug-eluting stent has been proposed as a potential method to prevent instent restenosis. Animal studies have confirmed safety and efficacy of sirolimus-eluting stent implantation in vivo. The FIM trial, which was the first clinical study on sirolimus-eluting stent in de novo lesions, has shown an astonishing 0% restenosis rate. The RAVEL trial was the first prospective, double-blind, multi-center trial that randomized 238 patients at 19 institutions with de novo lesions into sirolimus-eluting versus bare Bx velocity stent. Six-month binary restenosis rate in the sirolimus-group was again 0% compared to 26.6% in the control group. Angiographic late loss and major cardiac event were also significantly lower in the sirolimus-group. The SIRIUS trial is an ongoing study conducted in 53 US centers that randomized 1100 patients with de novo lesion into sirolimus-eluting and bare stents. Preliminary results also showed a significant reduction in binary restenosis, late loss and repeat revascularization rates. Apart from de novo lesions, early experience of sirolimus-eluting stent implantation for instent restenosis in non-randomized study was also promising, achieving a single-digit repeat restenosis rate. As compare with standard coronary stent, a sirolimus-eluting stent shows considerable promise for the prevention of neointimal proliferation, restenosis and associated clinical events.