This review provides a comprehensive overview of intrastent restenosis (ISR), a significant challenge in cardiovascular medicine. ISR refers to the re-narrowing of a blood vessel following stent placement, often leading to adverse cardiac events. The review discusses the pathophysiology of ISR, including mechanisms such as neointimal hyperplasia, which is driven by inflammation, smooth muscle cell proliferation, and extracellular matrix deposition. It also highlights the role of various risk factors, including patient-related, clinical, and angiographic factors, in the development of ISR. The review emphasizes the impact of stent type, with bare-metal stents (BMSs) having higher ISR rates compared to drug-eluting stents (DESs). DESs have significantly reduced ISR rates, but they are not without complications, such as late thrombosis and restenosis. The review also discusses the clinical presentation and diagnosis of ISR, noting that it can manifest as angina, heart failure, or acute myocardial infarction. Intravascular imaging techniques, such as optical coherence tomography (OCT) and intravascular ultrasound (IVUS), are highlighted as valuable tools for assessing ISR. Treatment options for ISR include DESs, drug-coated balloons (DCBs), and other interventions. The review compares the efficacy of these treatments, noting that while DESs have been effective in reducing ISR, DCBs offer an alternative with fewer complications. The review also discusses the importance of managing risk factors and the role of lifestyle modifications in preventing ISR. The review concludes that while significant progress has been made in understanding and treating ISR, it remains a significant challenge in cardiovascular medicine. Future research and the development of new stent technologies, such as bioresorbable stents, are essential to further reduce the incidence and impact of ISR. The review underscores the need for continued research and innovation to improve outcomes for patients with ISR.This review provides a comprehensive overview of intrastent restenosis (ISR), a significant challenge in cardiovascular medicine. ISR refers to the re-narrowing of a blood vessel following stent placement, often leading to adverse cardiac events. The review discusses the pathophysiology of ISR, including mechanisms such as neointimal hyperplasia, which is driven by inflammation, smooth muscle cell proliferation, and extracellular matrix deposition. It also highlights the role of various risk factors, including patient-related, clinical, and angiographic factors, in the development of ISR. The review emphasizes the impact of stent type, with bare-metal stents (BMSs) having higher ISR rates compared to drug-eluting stents (DESs). DESs have significantly reduced ISR rates, but they are not without complications, such as late thrombosis and restenosis. The review also discusses the clinical presentation and diagnosis of ISR, noting that it can manifest as angina, heart failure, or acute myocardial infarction. Intravascular imaging techniques, such as optical coherence tomography (OCT) and intravascular ultrasound (IVUS), are highlighted as valuable tools for assessing ISR. Treatment options for ISR include DESs, drug-coated balloons (DCBs), and other interventions. The review compares the efficacy of these treatments, noting that while DESs have been effective in reducing ISR, DCBs offer an alternative with fewer complications. The review also discusses the importance of managing risk factors and the role of lifestyle modifications in preventing ISR. The review concludes that while significant progress has been made in understanding and treating ISR, it remains a significant challenge in cardiovascular medicine. Future research and the development of new stent technologies, such as bioresorbable stents, are essential to further reduce the incidence and impact of ISR. The review underscores the need for continued research and innovation to improve outcomes for patients with ISR.