Restenosis following lower-extremity revascularization remains a significant and costly public health burden. Technical advances in endovascular therapy afford us the choice of treating longer and more distal lesions, which were heretofore reserved for vein bypass surgery. While contemporary vascular surgeons are well-versed in both open and percutaneous techniques, predictive models of who is at risk for failure from a specific mode of therapy are lacking. Traditional Framingham cardiovascular risk factors have not been successful in discriminating risk for failure of peripheral bypass or angioplasty. At the heart of this is our inability to make sophisticated measurements necessary to resolve phenotypic profiles into those likely to experience restenosis versus those likely to enjoy long-term patency. In this article we outline the available literature in an epidemiological framework of the association of traditional cardiovascular risk factors, emerging risk factors, as well as novel biomarkers with failure of both endovascular and open lower-extremity reconstructive procedures.