Although the recent studies have concerned the pathogenesis and therapeutic strategies of acute kidney injury (AKI), the mortality of AKI is still terribly high, and it is still one of the most important death factors in the intensive care unit. There is no doubt that early verdict of AKI, is good for a more aggressive treatment and can promise an improved prognosis for AKI patients. Serum creatinine level, serving as the gold standard for diagnosis of kidney injury, cannot meet current clinical work in its sensitivity and specificity of diagnosis of early AKI. Over the past decades, researchers worked to find and verify novel AKI biomarkers, including neutrophil gelatinase associated lipocalin, interleukin-18, kidney injury molecule-1 and cystatin-C, which were proved to be the potential reliable predictor of AKI development and prognosis, and were of great importance to the early diagnosis and clinical monitoring of AKI. This paper reviews the main studies on these novel prognostic predictors of AKI over the decades and evaluates their roles and limitations in early diagnosis and clinical prognosis prediction.