Restenosis remains a vexing problem in patients undergoing percutaneous coronary interventions (PCI). This phenomenon is related to a combination of events, including elastic recoil, negative remodeling and fibrointimal tissue proliferation. While stenting (bare metal and drug eluting) has made a dramatic impact in preventing recoil and remodeling, restenosis still occurs. Once restenosis occurs, it presents its own set of challenges due to the excess tissue proliferation. Major predicators of restenosis include diabetes, small stent diameter and long stented lesions. Vascular brachytherapy is the only proven therapy associated with a significant reduction in angiographic restenosis and the need for target vessel revascularization for the treatment of in-stent restenosis.