Epigenetics is the study of heritable changes in gene expression or cellular phenotype that occur without alterations in the DNA sequence. In the past decade, epigenetics has been identified as a key regulator of gene expression and therefore is likely to play a major role in multiple disease processes. More importantly, we now recognize epigenetics to be a sensitive, dynamic, and reversible process that has opened the door to multiple novel diagnostic, prognostic, and therapeutic strategies for human diseases. The focus of this review, however, is to explore the potential role of epigenetics in arteriovenous fistula (AVF) maturation. AVF maturation failure is currently the single most important cause of dialysis vascular access dysfunction and most important is the result of a peri-anastomotic stenosis thought to be caused by a combination of neointimal hyperplasia and inadequate outward remodeling. At a pathogenetic level, however, AVF maturation failure is likely the end result of the interaction between hemodynamic stressors (injury) and the vascular response to these stressors; the latter being influenced by uremia, oxidative stress, and inflammation. Interestingly, these same factors (hemodynamic shear stress, oxidative stress, inflammation, and uremia) are also important mediators of epigenetic modifications. We therefore believe that epigenetic factors potentially could play an important role in the pathogenesis of AVF maturation failure. The current review therefore tries to unravel some of these critical biological connections, with an emphasis on the future development of epigenetic-based diagnostic and therapeutic strategies for AVF maturation failure (a clinical problem for which there are currently no effective therapeutic interventions). © 2013.