Although arteriovenous (AV) fistulae are the preferred form of dialysis access, they continue to have significant problems with both early and late failures. Despite the magnitude of the clinical problem, however, there are unfortunately no effective therapies for AV fistula failure. We believe that this inability to intervene is partly due to a lack of understanding about the pathology and pathogenesis of AV fistula failure. Therefore, in the current review we will initially explore novel concepts about the pathology and pathogenesis of AV fistula failure. This information will then be used to suggest potential therapeutic interventions for this important, yet unmet clinical need. Finally, we will end with a brief description of some state-of-the-art clinical trials that are attempting to apply some of these novel therapeutic concepts to the recalcitrant clinical problem of AV fistula failure.