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The present review examines the major developments in early detection of neonatal sepsis, with an emphasis on the utility of diagnostic laboratory markers in clinical practice.Measures of acute phase proteins, cytokines, cell surface antigens, and bacterial genomes have been used alone or in combination to improve diagnosis of neonatal sepsis. Most studies evaluating laboratory diagnostic markers are retrospective cohorts or single center experience with relatively small sample size. Interpretation of these studies is confounded by inconsistent definitions of sepsis, heterogeneous sample populations, and different thresholds for diagnostic markers. Furthermore, many diagnostic markers are not available for routine care, they require specialized analytical procedures, and are expensive to perform.A better understanding of the neonatal inflammatory response to sepsis and identification of sensitive and specific markers of inflammation or rapid microbe-specific diagnostic tests would assist in the early detection of neonatal sepsis and in safely withholding antibiotics for patients in whom sepsis is unlikely.