Autologous arteriovenous fistula (AVF) is the preferred choice for providing vascular access to hemodialysis (HD) patients, but it is still affected by high incidence of non-maturation or early failure. After creation, AVF must undergo vascular remodeling, a process characterized by an increase in blood vessel diameter and wall thickness, to allow efficient and adequate HD. A growing body of evidence indicates that AVF maturation is related to the response of endothelial cells (ECs) to changes in wall shear stress (WSS), and in particular, to changes of its peak value. The reasons why important number of AVFs are affected by non-maturation or early failure still remain to be elucidated, but it has been suggested that local hemodynamic conditions with highly disturbed flow patterns may play an important role. In the present contribution, we addressed the role of WSS on AVF maturation, clarifying mechanisms that affect the clinical outcome of AVF creation. We also pointed out the need of non-invasive longitudinal studies, with repeated observations of hemodynamic parameters and structural changes during time, to obtain evidence of a cause-and-effect relationship between the presence of disturbed flow and AVF maturation failure. This understanding may be fundamental in the future to ameliorate clinical outcome of AVF creation, with a great impact on the clinical management of HD patients and their quality of life.