Patients with the most severe manifestations of lower extremity arterial occlusive disease often require peripheral bypass surgery for limb salvage and preservation of function. Although good quality saphenous vein offers the most durable conduit for reconstruction, 5-year failure rates are 30-50% and have remained largely unchanged for the past two decades. The majority of these failures occur within the first year of implantation, which is regarded as the most biologically active time during which the vein graft adapts to the arterial environment. Although intimal hyperplasia is generally regarded as the primary culprit of vein graft failure, geometric remodeling of the healing vein graft has recently emerged as a potentially significant contributing factor. While hemodynamic forces, including an increase in shear stress and wall tension, are undoubtedly central to the magnitude and direction of vein graft remodeling, we have determined that these forces alone cannot account for the extent of variability noted in early remodeling patterns. Therefore, we hypothesize that circulating factors, such as mediators of inflammation, may modulate the vein graft response to mechanical forces. This article reviews the definition and diagnosis of vein graft failure and summarizes our current efforts to understand the mechanisms of normal and abnormal vein graft adaptation to the arterial environment.