We examine established guidelines for evaluating infants at risk for early-onset sepsis (EOS), as well as newer risk-based assessment strategies that may safely reduce unnecessary antibiotic exposure for well-appearing newborns. We highlight a new multivariate risk assessment tool (Neonatal Early-Onset Sepsis Calculator) that can reduce empirical antibiotic therapy, laboratory testing, maternal-infant separation, and healthcare costs, without increasing adverse events. In the era of intrapartum antimicrobial prophylaxis for group B Streptococcus (GBS), the incidence of EOS among term and late preterm infants has decreased substantially. Established guidelines recommend laboratory evaluation and empirical antibiotics for all infants exposed to maternal chorioamnionitis, regardless of the infant’s clinical condition. Since the publication of these guidelines, newer evidence suggests that well-appearing infants can safely be managed with close clinical observation alone. The Neonatal Early-Onset Sepsis Calculator is a useful tool that quantifies an individual newborn’s EOS risk based on perinatal risk factors and clinical examination and has been shown to decrease laboratory evaluations and antibiotic use.