Acute kidney injury (AKI) has been associated with an increased risk of death and morbidity in many clinical scenarios. The prevention and treatment of AKI therefore has been advocated as a high-priority research focus. However, nearly all strategies tested in this setting have failed to prevent or cure AKI and fluid loading remains a cornerstone of preventive and curative treatment of AKI. Concerns have been raised, however, regarding both the efficacy and safety of fluid loading to prevent or reverse AKI. In this review, we address the question of the best use of fluid loading based on current preclinical and clinical data in a mechanistically guided approach. Impacts of fluid resuscitation on renal hemodynamics, from macrocirculation to microcirculation, with physiological end points as well as renal consequences of different fluids available are discussed. Finally, the complex relationship between renal hemodynamics is discussed. (C) 2016 Elsevier Inc. All rights reserved.