Early-onset sepsis (EOS) remains a major cause of neonatal morbidity and mortality. Even in the era of universal group B Streptococcus (GBS) screening and intrapartum antibiotic prophylaxis, EOS due to GBS and gram-negatives such as Escherichia coli is common. Both maternal and neonatal risk factors can be used to guide decisions regarding diagnostic evaluations and empiric antibiotic therapy for EOS. Prevention can be optimized by providing adequate prenatal care, reducing preterm deliveries, and providing intrapartum antibiotic prophylaxis when warranted.