Acute kidney injury (AKI) is a condition associated with significant morbidity and mortality. The incidence of AKI is increasing due to predisposing factors (sepsis, nephrotoxins, and hypotension). This review will focus on the risk stratification of patients vulnerable to developing AKI in whom the timing of the insult is known (e.g., cardiac surgery, contrast exposure) as well as the clinical context in which the risk intensifies. The review will also focus on preventive measures and different pharmacological agents for preventing AKI. Clinical trials of pharmacological agents for the prevention of AKI are challenging. While many compounds are promising in preclinical testing, only a few compounds have been tested, and none has shown consistent results in clinical trials. This is in part due to the lack of large and well-designed trials. With well-designed clinical trials, the use of novel biomarkers and innovative therapeutic strategies, we are on the verge of improving outcomes in the prevention of AKI.