Treatment of acute kidney injury has been hampered by the inability of a creatinine-based diagnosis to allow clinicians to intervene with timely treatments aimed at preventing further development of the disease to the point where renal replacement therapy is necessary or death occurs. Novel biomarkers of injury have been touted as the tool by which early detection can occur and, on that basis, novel treatments can be developed and delivered early in the disease process. Sufficient new biomarkers have been discovered and evaluated to expect that not one biomarker but a panel of biomarkers applied according to phase of injury, baseline renal function and comorbidities will be necessary for the early diagnosis of acute kidney injury. Issues of validation of these biomarkers remain, particularly in heterogeneous populations of critically ill patients. Nevertheless, we are rapidly moving towards an era where the diagnosis of acute kidney injury will be proactive rather than by the traditional diagnosis of exclusion.