Prevention of intraoperative injury to the vascular endothelium is of primary importance in maintaining viability and patency of the aorto-coronary saphenous vein graft. Surgical manipulation, ischemia, storage conditions, and distension before anastomosis can abnormally alter the antithrombogenic property of the endothelium leading to vasospasms, thrombogenesis, occlusive intimal hyperplasia, and stenosis. Endothelial injury can also form an initiation site for the formation of later-stage atheromas and graft failure. A multifactorial strategy aimed at prevention of endothelial injury and graft failure should include improved surgical techniques, optimal preservation conditions, avoidance of nonphysiologic distension pressures, and use of specific pharmacologic agents as the primary form of intervention. The successful application of this strategy, and the development of newer and more efficacious strategies that may impact on long-term graft patency, can now be aided by assessment of the structural and functional integrity of bypass conduits using multiphoton imaging techniques.