Early-onset sepsis can cause significant morbidity and mortality in newborn infants. Risk factors for sepsis include birth to mothers with inadequately treated maternal group B Streptococcus colonization, intra-amniotic infection, maternal temperature greater than 100.4°F (>38°C), rupture of membranes greater than 18 hours, and preterm labor. The organisms that most commonly cause early-onset sepsis include group B Streptococcus, Escherichia coli, and viridans streptococci. Infants often present within the first 24 hours after birth with clinical signs of sepsis, with respiratory distress as the most common presenting symptom. However, infants can also have respiratory distress from noninfectious etiologies. Therefore, when physicians are faced with asymptomatic infants with risk factors or infants with respiratory distress without risk factors, there is a delicate balance between empirically treating with antibiotics and observing these infants without treating.