PURPOSE OF REVIEW: Drug-eluting stent (DES) technology has greatly enhanced the safety and effectiveness of percutaneous coronary interventions (PCI). The aim of the present paper is to provide a comprehensive review of in-stent restenosis (ISR), focusing on the contemporary DES era, including its incidence, mechanisms, and imaging characterization. RECENT FINDINGS: Despite the widespread use of DES and numerous improvements, recent clinical data indicate that ISR still occurs in 5-10% of PCI procedures, posing a considerable public health issue. The incidence, morphology, and clinical implications of ISR are determined by a complex interplay of several factors: the patient, stent, procedure, and vessel and lesion-related factors. Advancements in intracoronary imaging have provided greater insight into its patterns and underlying causes. Over time, treatment strategies have evolved, and current guidelines recommend an individualized approach using intracoronary imaging to characterize ISR's underlying substrate.