This paper provides a comprehensive review of intrastent restenosis (ISR), addressing its contemporary advancements, developments, and prevailing trajectories. The authors aim to offer a thorough overview of recent developments, including pathophysiological insights, therapeutic approaches, and new strategies to tackle the complex challenges of ISR in modern clinical settings. ISR is defined as the narrowing of a blood vessel's diameter following an angioplasty procedure, often occurring within 3 to 12 months post-angioplasty. The incidence of ISR depends on various factors, such as stent type, patient characteristics, and cardiovascular risk factors. The introduction of drug-eluting stents (DESs) has significantly reduced ISR rates from 5 to 30 percent with bare-metal stents (BMSs) to 2 to 10 percent with DESs. However, DES-related failures still pose a concern, affecting up to 10% of all implanted stents. The pathophysiology of ISR involves tissue proliferation, neointimal hyperplasia, and inflammatory responses, which are influenced by factors such as mechanical injury, local and systemic pro-inflammatory responses, and hypersensitivity reactions to stent components. Risk factors for ISR include patient-related factors (e.g., chronic kidney disease, diabetes, hypertension), clinical factors (e.g., gender, diabetes, antiplatelet medication use), and angiographic factors (e.g., stent deployment complexity). Diagnostic methods, including coronary angiography and intravascular imaging, play a crucial role in identifying and managing ISR. Treatment options include the use of DESs and drug-coated balloons (DCBs), with DESs being the preferred choice due to their superior outcomes in reducing target lesion revascularization (TLR) rates and residual stenosis. The paper emphasizes the importance of managing risk factors, implementing appropriate lesion preparation, and using intracoronary imaging to ensure accurate stent apposition. Despite advancements, ISR remains a significant challenge, and further research is needed to develop innovative solutions.This paper provides a comprehensive review of intrastent restenosis (ISR), addressing its contemporary advancements, developments, and prevailing trajectories. The authors aim to offer a thorough overview of recent developments, including pathophysiological insights, therapeutic approaches, and new strategies to tackle the complex challenges of ISR in modern clinical settings. ISR is defined as the narrowing of a blood vessel's diameter following an angioplasty procedure, often occurring within 3 to 12 months post-angioplasty. The incidence of ISR depends on various factors, such as stent type, patient characteristics, and cardiovascular risk factors. The introduction of drug-eluting stents (DESs) has significantly reduced ISR rates from 5 to 30 percent with bare-metal stents (BMSs) to 2 to 10 percent with DESs. However, DES-related failures still pose a concern, affecting up to 10% of all implanted stents. The pathophysiology of ISR involves tissue proliferation, neointimal hyperplasia, and inflammatory responses, which are influenced by factors such as mechanical injury, local and systemic pro-inflammatory responses, and hypersensitivity reactions to stent components. Risk factors for ISR include patient-related factors (e.g., chronic kidney disease, diabetes, hypertension), clinical factors (e.g., gender, diabetes, antiplatelet medication use), and angiographic factors (e.g., stent deployment complexity). Diagnostic methods, including coronary angiography and intravascular imaging, play a crucial role in identifying and managing ISR. Treatment options include the use of DESs and drug-coated balloons (DCBs), with DESs being the preferred choice due to their superior outcomes in reducing target lesion revascularization (TLR) rates and residual stenosis. The paper emphasizes the importance of managing risk factors, implementing appropriate lesion preparation, and using intracoronary imaging to ensure accurate stent apposition. Despite advancements, ISR remains a significant challenge, and further research is needed to develop innovative solutions.