Despite major technological advances in the practice of percutaneous coronary intervention, restenosis of the treated arteries remains a challenge for many interventional cardiologists. Sirolimus is a macrolide antibiotic with potent antifungal, immunosuppressive, and antimitotic activities. Sirolimus inhibits in-stent restenosis via 2 major mechanisms of action: by blocking the process of neointimal hyperplasia by inhibiting smooth muscle cell proliferation and by inhibiting inflammatory cell activity. In pivotal clinical trials, the sirolimus-eluting stent has demonstrated significant improvements in angiographic and clinical outcomes compared with bare metal stents in patients with de novo lesions in native coronary arteries. Since the systemic exposure of sirolimus in patients who received the drug-eluting stent is minimal, adverse effects resulting from systemic exposure of sirolimus are unlikely to occur. Further studies are needed to determine the safety and effectiveness of sirolimus-eluting stents in patients with more complex coronary artery lesions. In addition, the long-term safety, efficacy, and cost-effectiveness of this novel drug-eluting device will need to be established in ongoing clinical trials. This review article focuses on the pharmacology as well as clinical studies of the sirolimus-eluting stent.