Coronary in-stent restenosis (ISR) remains a major contributor to repeat revascularisation despite advances in drug-eluting stent (DES) technology. Its persistence reflects a complex and heterogeneous interplay among mechanical, biological, and procedural factors, and understanding the dominant mechanism in each case is fundamental to effective treatment selection. This narrative review provides a contemporary, mechanism-guided approach to the practical management of coronary ISR. We summarise the definition, incidence, and classification of ISR—including the Mehran, Waksman, and SCAI 2023 time-based frameworks—and outline patient-related, procedural, anatomical, and stent-related risk factors. The pathophysiology of neointimal hyperplasia and neoatherosclerosis is discussed with reference to its clinical implications. Intracoronary imaging with intravascular ultrasound (IVUS) or optical coherence tomography (OCT) is central to ISR characterisation and treatment planning. Current international guidelines support imaging use in ISR management, though it is important to recognise that this recommendation is based largely on observational and surrogate-endpoint data rather than ISR-specific randomised trials demonstrating reductions in hard clinical outcomes, and practical barriers including cost, availability, and operator expertise must be acknowledged. Evidence-based treatment strategies—including drug-coated balloons (DCB), repeat DES implantation, lesion-modifying therapies, vascular brachytherapy, and coronary artery bypass grafting—are reviewed critically with reference to contemporary trial data and their specific clinical applicability. The choice between DCB and repeat DES is addressed with greater nuance, accounting for ISR type (BMS-ISR versus DES-ISR), lesion pattern, stent layering, and bleeding risk. Management considerations in complex subsets—chronic total occlusion ISR, left main ISR, saphenous vein graft ISR, and recurrent ISR—are also addressed. We propose a practical, substrate-driven management framework aligned with the 2024 ESC, 2021 ACC/AHA/SCAI, and 2018 JCS/JSCVS guidelines. Future research priorities include ISR-specific randomised trials with hard clinical endpoints, prospective validation of imaging-guided treatment algorithms, head-to-head comparisons of DCB platforms, and investigation of pharmacological strategies targeting neoatherosclerosis progression.