Although drug-eluting stents (DES) have significantly reduced the incidence and prevalence of coronary in-stent restenosis (ISR), ISR still occurs in approximately 10% of patients in real-world practice. Areas covered: The development of newer generations of DES, drug-coated balloons (DCB) and increased use of intracoronary imaging have improved our treatment options for and pathophysiologic understanding of ISR. These technological advancements have also largely supplanted older modalities for treatment of ISR, such as brachytherapy, bare metal stents, conventional and cutting balloon angioplasty, and atherectomy devices. This article reviews the presentation, pathophysiology, and treatment of coronary artery ISR, with a focus on recent clinical data and emerging therapies for this difficult to treat clinical problem. Expert commentary: DCB and second-generation DES are the most effective treatment options for ISR. Most trials support a slight superiority of second-generation DES, while DCB have the advantage of not adding another metal layer. The role of bioresorbable vascular scaffolds will be determined in the near future.