Imagine for a moment you are counseling a patient with a suspicious mass and symptoms that are concerning but nonspecific. Although there are several possible diagnoses, one hangs unspoken between you and the patient-a diagnosis that carries significant morbidity and mortality. You propose an immediate biopsy. After all, a tissue diagnosis is the criterion standard, and this matter is urgent. The patient agrees, and as the patient begins to stand, you raise a hand and mention another test you would like to order. The patient is curious. "What are the benefits of this test?" You explain that the test involves sending a portion of the biopsied tissue to a separate part of the laboratory, where the pathology department will look for other markers of disease. Of course, the patient nods; that makes sense. "If this extra test result is negative, I will be okay, right?" "No," you answer, "a negative test result does not mean the biopsy result will be negative." The patient frowns. "Well, is it a bad sign if the test result is positive?" "Not necessarily," you explain. "Many things can make the other test results abnormal, so we'll still have to wait on the biopsy results. The biopsy is the key." The patient sits down again, looking confused. "If the biopsy is so important, why are we wasting tissue on this other test?" "Well," you glance helplessly toward the window then look back to your frowning patient. "It's just what we've always done in these cases."This exchange is hypothetical, but in the case of Creactive protein (CRP) for neonatal sepsis, it is all too real. The nonspecific signs of late-onset infection in infants, particularly those born preterm, combined with the high risk of morbidity and mortality have underscored the need for accurate diagnosis of neonatal sepsis. 1 Culture of blood and other sterile sites is the criterion standard for neonatal sepsis. However, myriad ancillary laboratory tests have been suggested as potential biomarkers for neonatal sepsis; these include CRP, complete blood counts with differential, procalcitonin, a variety of interleukins, and presepsin. 2 The value of those tests in the clinical management of suspected sepsis is questionable. In this issue of JAMA Pediatrics, Brown et al 3 report their systematic review and meta-analysis of the sensitivity, specificity, and test accuracy of CRP for late-onset neonatal sepsis. They analyzed 22 studies including 2255 infants, the majority being 32 weeks or less gestational age or 1500 g or less birth weight. The median specificity of CRP was 0.74 and median sensitivity was 0.62. Assuming a cohort of 1000 preterm infants with a 20% prevalence rate of late-onset sepsis, this means that 76 cases of infection would be missed, and 208 infants would be incorrectly diagnosed as having sepsis-more than the number of infants with sepsis (200).