<p>Neonatal early-onset sepsis (EOS) continues to be a significant source of morbidity and mortality among newborns, especially among very low-birth-weight infants. Epidemiologic risk factors for EOS have been defined, and considerable resources are devoted to the identification and evaluation of infants at risk for EOS. The widespread implementation of intrapartum antibiotic prophylaxis for the prevention of early-onset neonatal group B streptococcal disease has reduced the overall incidence of neonatal EOS and influenced the microbiology of persistent early-onset infection. Recommendations for perinatal risk factor–based evaluation and empiric antibiotics treatment of neonates result in a large proportion of uninfected infants undergoing medical intervention, including antibiotic therapy. Objective risk assessment tools have been developed that may allow safe restriction of medical intervention in uninfected newborns, promote antibiotic stewardship, and optimize resource use.</p>