While randomized controlled trials (RCTs) are the gold standard for evidence in medicine, there is an overall paucity of RCTs in nephrology compared with other medical subspecialties. Consequently, the management of the dialysis population is often guided by nephrology clinical practice guidelines that are largely based on observational data or expert opinion. This review examines problems related to designing, conducting and completing RCTs in nephrology, highlighting major challenges, successes and frustrations, with specific examples as they pertain to the science of hemodialysis vascular access and their impact on clinical practice guidelines.