Hemodialysis vascular access dysfunction is a major source of morbidity for patients with ESRD. Development of effective approaches to prevent and treat vascular access failure requires an understanding of the underlying mechanisms, suitable models for preclinical testing, systems for targeted delivery of interventions to maximize efficacy and minimize toxicity, and rigorous clinical trials that use appropriate outcome measures. This article reviews the substantial progress and ongoing challenges in developing novel treatments for arteriovenous vascular access failure and focuses on localized rather than systemic interventions.