The incidence of restenosis after percutaneous peripheral interventions (PPI) varies considerably depending upon the vascular bed but appears to be highest in the femoropopliteal and tibioperoneal arteries. The restenosis process in the periphery does not appear to stop at the 6-month mark, as seen with bare metal stents in the coronary arteries, but continues for a longer time, possibly years, after the intervention. This review evaluates the incidence of restenosis following lower extremity arterial interventions and potential drugs or devices that could alter this process, including nonpharmacological (stents, cryoplasty, Cutting Balloon angioplasty, atherectomy, brachytherapy, and photodynamic therapy) and pharmacological (systemic and direct drug delivery) approaches. A global strategy to achieve optimal outcome with PPI is offered: (1) obtain excellent acute angiographic results with less dissection and recoil, (2) protect the distal tibial vascular bed, and (3) reduce smooth muscle cell proliferation with pharmacological intervention.