© 2016 by the American Society of Nephrology. Vascular access dysfunction remains amajor cause ofmorbidity andmortality in hemodialysis patients. At present there are feweffective therapies for this clinical problem. The poor understanding of the pathobiology that leads to arteriovenous fistula (AVF) and graft (AVG) dysfunction remains a critical barrier to development of novel and effective therapies. However, in recent years we have made substantial progress in our understanding of the mechanisms of vascular access dysfunction. This article presents recent advances and new insights into the pathobiology of AVF and AVGdysfunction and highlights potential therapeutic targets to improve vascular access outcomes.