Hemodialysis (HD) access complications constitute a major cause of morbidity in HD patients. The failure of HD access grafts is predominantly due to progressive intimal hyperplasia (IH) at the venous anastomosis, resulting in a graft flow decline, which ultimately gives rise to graft thrombosis. To date, all tested pharmacological and surgical interventions have not resulted in increased arteriovenous (AV) graft patency rates in HD patients. In this review, we address the mechanisms contributing to AV graft failure and discuss several "emerging" strategies, which could hold promise for optimizing AV graft patency rates. In view of the failure of systemic therapies and the predictable localization of IH, local therapeutic strategies comprise the most promising interventions to improve AV graft patency rates. Based on the large number of promising candidates including drug-eluting stents and brachytherapy, the unmet clinical need for AV graft failure in HD patients is likely to be revisited in the very near future. The biggest challenge, however, remains to translate basic experimental findings into clinical benefits. Simultaneously, continuous efforts should be undertaken to increase the percentage of patients utilizing AV fistulas, which remains the best form of permanent vascular access (VA) for HD.