Many specific interventions and drugs have been used to protect the kidney in high-risk situations (prophylaxis) or to attenuate loss of function in patients with acute kidney injury (AKI), but very few have been tested in large multicenter double-blind randomized controlled trials (MC-DB-RCTs). Nephrotoxins must be removed whenever possible. Iso-osmolar nonionic contrast media attenuate the incidence and severity of contrast-induced nephropathy (CIN). Fluid loading with intravenous normal saline at 1 ml/kg/h has been shown to attenuate CIN in a large single-center RCT. No other prophylactic or therapeutic intervention has been consistently shown to be protective to the kidney. Low-dose dopamine has been strongly shown not to deliver any protection from kidney injury in a large MC-DB-RCT. A better understanding of the pathogenesis of AKI in different clinical states and the availability of biomarkers which allow the early diagnosis of AKI are both sorely needed if future interventions are to prove more effective.