The incidence of acute kidney injury (AKI) is increasing steadily. This can be attributed to a growing prevalence of risk factors for AKI, such as aging, diabetes, underlying cardiovascular disease and the escalating application of more complex procedures. Currently, there is no treatment for established AKI, except for renal replacement therapy in case of life-threatening conditions. The focus should thus be shifted towards AKI prevention rather than treatment. Several promising pharmacological and non-pharmacological interventions for prevention of AKI in animal models did not fulfill the expectations when applied in humans. There are multiple reasons why these interventions prove to be disappointing. The pathophysiology of AKI in different settings has not been fully elucidated, the underlying cause of AKI in the clinical setting is often multifactorial, and animal AKI models often do not mimic human AKI very well. Ischemia-reperffision models are representative for human AKI in the setting of aortic clamping or in case of delayed graft function after kidney transplantation, but are not suited to study AKI in many other conditions such as sepsis. Moreover, several drugs for AKI prevention are associated with deleterious adverse events in humans as they lack selectivity. In this review, an overview of the strategies that can be used in the clinical setting for AKI prevention will be presented. Potential preventive strategies in certain specific clinical conditions will also be reviewed.