BACKGROUND. NAFLD ranges from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH). The natural history of NAFLD and the optimal strategy to identify subjects with progressive liver disease are unclear. Objectives. To assess the evidence in: (1) natural history of NAFLD; and (2) non-invasive methods to differentiate NAFLD histological subtypes. DESIGN AND SETTING. Among 4185 articles published on MEDLINE, Cochrane Library, EMBASE, Pubmed, national and International meeting abstracts through July 2010, 40 articles assessing the natural history of NAFLD and 32 articles evaluating the diagnostic accuracy of non-invasive tests against liver biopsy (LB) were included. MEASUREMENTS. Two reviewers retrieved articles and evaluated study quality by appropriate scores. Main outcomes were pooled using random- or fixed-effects models. RESULTS. NAFLD has an increased overall mortality (OR: 1.57, 95% CI: 1.18-2.10), deriving from liver-related and cardiovascular disease, and a 2-fold risk of diabetes. Compared to SS, NASH has a higher liver-related (OR for NASH: 5.71, 2.31-14.13; OR for NASH with advanced fibrosis: 10.06, 4.35-23.25), but not cardiovascular mortality (OR: 0.91, 0.42-1.98). Three non-invasive methods received independent validation: pooled AUROC, sensitivity and specificity of cytokeratin-18 for NASH are 0.82 (0.78-0.88), 0.78 (0.64-0.92), 0.87 (0.77-0.98). For NASH with advanced fibrosis, pooled AUROC, sensitivity and specificity of NAFLD fibrosis score and Fibroscan are 0.85 (0.80-0.93), 0.90 (0.82-0.99), 0.97 (0.94-0.99) and 0.94 (0.90-0.99), 0.94 (0.88-0.99) and 0.95 (0.89-0.99). CONCLUSIONS. NAFLD warrants screening for cardio-metabolic risk and for progressive liver disease. The combination of three noninvasive tests with LB may optimally individuate patients with NASH, with or without advanced fibrosis.