The vasodilatory, natriuretic, and diuretic properties of natriuretic peptides (NPs) make them attractive agents in the treatment of acute kidney injury (AKI). However, there is conflicting evidence of their beneficial effects. This article examines the reasons for the differences, and provides insight that the reported outcomes may be related to the unique physiologic effects and mechanisms of action of NPs, the designs and cohorts of the trials, and the characteristic renal hemodynamics associated with AKI. NPs are effective in the prevention of AKI when applied prophylactically, in lower doses, for prolonged duration, in patients with mild to moderate impairment in renal function, and in predictable clinical settings with clearly defined outcome measurements.