Traditional diagnosis of acute kidney injury (AKI) depends on detection of oliguria and rise of serum creatinine level, which is an unreliable and delayed marker of kidney damage. Delayed diagnosis of AKI in the critically ill patient is related to increased morbidity and mortality, prolonged length of stay, and cost escalation. The discovery of a reliable biomarker for early diagnosis of AKI would be very helpful in facilitating early intervention, evaluating the effectiveness of therapy, and eventually reducing cost and improving outcome. Innovative technologies such as genomics and proteomics have contributed to the discovery of new biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (Cys C), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and liver-type fatty acid binding protein (L-FABP). The current status of the most promising of these novel AKI biomarkers, including NGAL, Cys C, KIM-1, L-FABP, and IL-18, is reviewed.