Since 1992, professional societies or public health agencies in the United States– and elsewhere– have issued several generations of recommendations for prevention or management of early-onset neonatal sepsis (EOS). Despite those efforts, recommendations remain inconsistent, clarifications are necessary, local adaptations are common, and compliance rates are low. We postulate that lack of consensus, especially regarding postnatal management of the neonate, is largely a result of two sets of factors. First, obstetrical prevention strategies have substantially reduced incidence of EOS, potentially changing the utility of predictive strategies based on risk factors. Second, recent data better delineate relationships among risk factors, clinical signs, and EOS, suggesting that risk predictors may have different utilities in different groups. The purpose of this commentary is to explore these questions and to suggest new approaches to management of newborns who may be at risk for EOS.