Lower extremity vascular grafts, either vein or synthetic, fail for diverse reasons. Technical defects or poor surgical judgment doom a graft beyond any benefit pharmacotherapy can offer. Graft failure due to spontaneous thrombosis particularly affects prosthetic conduits, and use of antiplatelet agents (dextran, ASA) or anticoagulants (heparin, warfarin) is probably useful in this setting. An effective way to inhibit vein graft or anastomotic intimal hyperplasia remains elusive. Perhaps the most permanent and longstanding influence on lower extremity graft survival can be made through risk factor intervention aimed at arresting the progression of atherosclerosis. Aggressive treatment of hyperlipidemia, hypertension, smoking, and other known risk factors should be routinely and aggressively pursued in patients with lower extremity grafts, either autogenous or prosthetic. Lower extremity graft patency is optimally ensured by technically adept insertion of a proper autologous conduit in a well-selected patient. Pharmacotherapy may have a significant adjunctive role in the maintenance of graft patency, especially in high-risk settings such as limb salvage with associated poor outflow, a marginal vein graft, or the obligatory use of prosthetic material.