Since the Fistula First Initiative was formulated in 2003, providers and payers have increasingly emphasized the need to create more arteriovenous fistulae. To maximize the chances of successful fistula maturation, a thorough understanding of the biology and surgical aspects of fistula placement are essential. A functional endothelium in the target vessels is the prerequisite for the adaptive remodeling of the vessel wall, which has to take place after fistula formation. Mechanoreceptors of the endothelium sense the increase in shear stress and, through a variety of activated signaling cascades, induce the necessary changes and vasodilation of the respective vessels. The successful fistula placement starts with a thorough preoperative evaluation, which focuses on protecting the target vessels and avoiding intravenous catheters and devices. Intraoperatively, the risk of endothelial dysfunction and hyperplasia is further minimized through an atraumatic dissection with minimal manipulation of the vein and artery. The surgical technique should also focus on decreasing the vessel compliance mismatch and avoiding an inflammatory response secondary to hematoma formation. Postoperatively, the fistula must be diligently monitored for the complications of thrombosis, postoperative steal syndrome, neuropathy, aneurysm formation, infection, and high-output cardiac failure. Early recognition of a problem is the key to saving an otherwise doomed fistula. An armamentarium of percutaneous techniques is available to the access surgeon to treat the most common causes of failed access formation. However, in some cases a surgical revision of the access site through patch angioplasty, a jump graft, and graft interposition is necessary to create a fistula which can be successfully used for hemodialysis. © 2010 Wiley Periodicals, Inc.