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SEPSIS IS ONE OF THE MOST COMMON diagnostic challenges in the NICU. Currently a definitive diagnosis can be made only with the gold-standard blood culture, which is generally not available for 48 hours.1,2 Difficulty obtaining a large enough sample to detect a positive blood culture, as well as increased use of antenatal antibiotics, has complicated the ability to make a definitive diagnosis of sepsis.3 If left untreated, sepsis can increase morbidity and mortality. Therefore, many infants are treated empirically with broad-spectrum antibiotics.4,5 Two kinds of tests would be most helpful in the diagnosis of neonatal sepsis: one that quickly confirms the diagnosis and one that conclusively rules it out. In fact, a diagnostic sepsis marker with a high negative predictive value (the value representing patients without sepsis who are correctly diagnosed) might reduce the short- and long-term adverse effects of antibiotics, health care costs, and length of hospital stay.6 Despite extensive investigation no single test meets the criteria that would make it an ideal marker for the early diagnosis of sepsis in the newborn.5,7,8 Generally, screening includes a complete blood count with differential and may be accompanied by other adjunctive tests such as a C-reactive protein (CRP).9–11 This column examines CRP, an acute phase reactant (APR), as a diagnostic marker for neonatal sepsis.