Despite all the progress achieved since Scribner first introduced the arteriovenous (AV) shunt in 1960 and Cimino and Brescia introduced the native AV fistula in 1962, we have continued to face a conundrum in vascular access for dialysis, in that dialysis vascular access is at the same time both the 'lifeline' and the 'Achilles' heel' of haemodialysis. Indeed, findings from a multitude of published articles in this area, unfortunately mainly observational studies, reflect both our frustration and our limited knowledge in this area. Despite improved understanding of the pathophysiology of stenosis and thrombosis of the vascular access, we have unfortunately not been very successful in translating these advances into either improved therapies or a superior process of care. As a result, we continue to face an epidemic of arteriovenous fistula (AVF) maturation failure, a proliferation of relatively ineffective interventions such as angioplasty and stent placement, an extremely high incidence of catheter use, and more doubts rather than guidance with regard to the role (or lack thereof) of surveillance. An important reason for these problems is the lack of focused translational research and robust randomized prospective studies in this area. In this Review, we will address some of these critical issues, with a special emphasis on identifying the best process of care pathways that could reduce morbidity and mortality. We also discuss the potential use of novel therapies to reduce dialysis vascular access dysfunction.