Over the last decade, stenting has emerged as the dominant form of percutaneous coronary intervention (PCI) and is currently performed in 80% of all PCIs. As a result, treatment of in-stent restenosis (ISR) has become an increasingly frequent challenge for the interventional cardiologist. Any anti-restenosis therapy under consideration must contend with the two basic mechanisms of vessel re-narrowing following coronary intervention: vascular contraction, which can be mechanically blocked with a typical balloon expandable stent; and neointimal proliferation, which is a complex cellular reaction to the injury caused by the actions of mechanical devices such as balloons, stents, and atherectomy catheters. Recently, several randomized clinical trials have demonstrated that intracoronary brachytherapy can substantially reduce the rates of both angiographic and clinical restenosis in patients undergoing PCI for ISR. Vascular radiotherapy is the first proven, clinically effective anti-restenosis therapy. Despite its established efficacy, there remains much room for improvement in the aspects of safety and cost effectiveness. We have developed novel methods of brachytherapy using local delivery of 99mTc-HMPAO and 166Ho-coated balloon, which are safe and effective in the prevention of coronary stent restenosis.