Endovascular treatment of lower extremity arteries is a common treatment method for patients with arteriosclerosis obliterans of the lower extremities. The treatment of balloon dilation plus stent implantation is often unsatisfactory due to its high in-stent restenosis (ISR) rates. ISR seriously affects the prognosis and quality of life of the patients after operation. Patients with ISR usually need a second operation. However, due to a series of problems such as high cost, poor long-term patency rates, and stent fracture, the prevention of ISR is particularly important. Sulodexide has extensive biological effects on cardiovascular system, and its anti-inflammatory, anti-thrombotic, and vascular endothelial protection exerts important beneficial effects on prevention and treatment of ISR. The authors review the current status in diagnosis and treatment of ISR and the application prospects of sulodexide in treatment of ISR.