In the last years the development of new techniques and technologies for the endovascular treatment of peripheral arterial occlusive disease has allowed to treat a vast array of lesions with high technical success and low complications. Despite these advances, restenosis, and in particular in-stent restenosis, is a problem that significantly affects middle and long-term results and remains to be solved. Drug-eluting balloons (DEB) have shown good results in the treatment of coronary in-stent restenosis in experimental and clinical trials, but only few experimental and clinical trials focus on the peripheral district. This review summarizes the available experimental and clinical data in support of DEB in the treatment of ISR in the peripheral district. Larger clinical trials focused on paclitaxel-coated balloon in the treatment of ISR in the peripheral arteries will be necessary to provide definitive evidence of clinical benefit.