Acute kidney injury (AKI) is a common event associated with high morbidity and mortality. Ischemia is a major cause of AKI. TRPM2, a member of the transient receptor potential- melastatin subfamily, is activated by oxidant stress, ADP-ribose, TNF and intracellular calcium, all of which are increased during kidney ischemia. We found that genetic or pharmacologic inhibition of TRPM2 dramatically reduces ischemic kidney injury. The mechanism involves, at least in part, a TRPM2-dependent increase in Rac1 activity resulting in increased NADPH oxidase activity and oxidant stress.