Group B Streptococcus (GBS) is a major cause of neonatal sepsis in both term and preterm infants. Prevention strategies include routine antepartum GBS screening and intrapartum antibiotic prophylaxis (IAP), which have reduced neonatal GBS disease over the past three decades. However, GBS disease persists, causing mortality and morbidity. This review highlights the epidemiology, pathogenesis, and clinical presentation of neonatal GBS disease, along with obstetric recommendations for screening, IAP, and management of at-risk infants. Early-onset GBS disease (EOGBS) occurs within the first 6 days of life, with a significant decrease in incidence in the U.S. from 1.8 cases per 1000 live births in 1992 to 0.2 cases per 1000 live births in 2020. EOGBS is most common in term infants, accounting for 51% of cases. Late-onset GBS disease (LOGBS), occurring 7–89 days after birth, is now the predominant form of neonatal GBS disease, accounting for 57% of cases in 2020. LOGBS is more common in preterm infants, who are at six times higher risk than term infants. GBS is a beta-hemolytic, encapsulated Gram-positive bacterium that colonizes the genitourinary and gastrointestinal tracts. It produces toxins that cause direct tissue injury and evades the host immune system via its polysaccharide capsule. GBS is transmitted from mother to infant during birth, with maternal colonization rates ranging from 10–35%. IAP significantly reduces neonatal colonization and EOGBS, but LOGBS remains stable. Transmission can also occur postpartum, via breast milk, or in healthcare settings. Clinical presentations of EOGBS include isolated bacteremia (80–90%) and meningitis (1–10%). LOGBS presents with isolated bacteremia (61%), meningitis (31%), and other infections. Infants with LOGBS may have negative blood cultures, emphasizing the need for urine, CSF, and focal site cultures. Clinical signs include fever, poor feeding, respiratory distress, and seizures. Management of at-risk infants involves risk stratification based on clinical status and maternal factors. Empiric antibiotic therapy is recommended for infants at high risk of EOGBS, with ampicillin and aminoglycoside for those aged 0–7 days. For older infants, ampicillin and cephalosporin are used. For confirmed GBS disease, antibiotic therapy is tailored based on susceptibility, with durations of 10 days for bacteremia and 14 days for meningitis. GBS remains susceptible to first-line IAP agents, with rare resistanceGroup B Streptococcus (GBS) is a major cause of neonatal sepsis in both term and preterm infants. Prevention strategies include routine antepartum GBS screening and intrapartum antibiotic prophylaxis (IAP), which have reduced neonatal GBS disease over the past three decades. However, GBS disease persists, causing mortality and morbidity. This review highlights the epidemiology, pathogenesis, and clinical presentation of neonatal GBS disease, along with obstetric recommendations for screening, IAP, and management of at-risk infants. Early-onset GBS disease (EOGBS) occurs within the first 6 days of life, with a significant decrease in incidence in the U.S. from 1.8 cases per 1000 live births in 1992 to 0.2 cases per 1000 live births in 2020. EOGBS is most common in term infants, accounting for 51% of cases. Late-onset GBS disease (LOGBS), occurring 7–89 days after birth, is now the predominant form of neonatal GBS disease, accounting for 57% of cases in 2020. LOGBS is more common in preterm infants, who are at six times higher risk than term infants. GBS is a beta-hemolytic, encapsulated Gram-positive bacterium that colonizes the genitourinary and gastrointestinal tracts. It produces toxins that cause direct tissue injury and evades the host immune system via its polysaccharide capsule. GBS is transmitted from mother to infant during birth, with maternal colonization rates ranging from 10–35%. IAP significantly reduces neonatal colonization and EOGBS, but LOGBS remains stable. Transmission can also occur postpartum, via breast milk, or in healthcare settings. Clinical presentations of EOGBS include isolated bacteremia (80–90%) and meningitis (1–10%). LOGBS presents with isolated bacteremia (61%), meningitis (31%), and other infections. Infants with LOGBS may have negative blood cultures, emphasizing the need for urine, CSF, and focal site cultures. Clinical signs include fever, poor feeding, respiratory distress, and seizures. Management of at-risk infants involves risk stratification based on clinical status and maternal factors. Empiric antibiotic therapy is recommended for infants at high risk of EOGBS, with ampicillin and aminoglycoside for those aged 0–7 days. For older infants, ampicillin and cephalosporin are used. For confirmed GBS disease, antibiotic therapy is tailored based on susceptibility, with durations of 10 days for bacteremia and 14 days for meningitis. GBS remains susceptible to first-line IAP agents, with rare resistance