Despite the advent of intracoronary brachytherapy, treatment of in-stent restenosis, particularly diffuse in-stent restenosis, remains problematic. Adjunctive debulking prior to brachytherapy may improve long-term outcomes. We review the literature and report our results of a series of patients treated with excimer laser coronary atherectomy along with balloon angioplasty and brachytherapy for in-stent restenosis. We conclude that adjunctive debulking may improve the long-term clinical outcomes of patients with diffuse in-stent restenosis treated with angioplasty and intracoronary radiation. A randomized controlled trial is warranted.