Early-onset neonatal sepsis remains a significant and serious issue, particularly for preterm infants. Group B streptococcus (GBS) is the most common cause, while *Escherichia coli* is the leading cause of mortality. Maternal intrapartum antimicrobial prophylaxis has reduced GBS disease but increased Gram-negative infections, especially in very-low-birth-weight infants. Diagnosis involves clinical presentation, non-specific markers like C-reactive protein and procalcitonin, blood cultures, and molecular methods such as PCR. Viruses, including enteroviruses, parechoviruses, and herpes simplex virus (HSV), should be considered in the differential diagnosis. Empirical treatment typically includes ampicillin and gentamicin or ampicillin and cefotaxime for meningitis. Research is focused on developing GBS vaccines. Early-onset neonatal sepsis is more common in preterm infants and is often caused by GBS and *E. coli*. Viral and fungal infections, though less common, can also cause early-onset sepsis. Clinical presentation varies by gestational age and severity, with preterm infants often showing apnea, bradycardia, and cyanosis as initial signs. Laboratory findings include white blood cell counts, differential, platelet counts, and blood cultures. Acute-phase reactants like CRP and procalcitonin are used to assist in diagnosis. Molecular methods, including PCR and DNA microarrays, offer rapid and sensitive detection of pathogens. Urine testing is not necessary in the first few days but should be considered later.Early-onset neonatal sepsis remains a significant and serious issue, particularly for preterm infants. Group B streptococcus (GBS) is the most common cause, while *Escherichia coli* is the leading cause of mortality. Maternal intrapartum antimicrobial prophylaxis has reduced GBS disease but increased Gram-negative infections, especially in very-low-birth-weight infants. Diagnosis involves clinical presentation, non-specific markers like C-reactive protein and procalcitonin, blood cultures, and molecular methods such as PCR. Viruses, including enteroviruses, parechoviruses, and herpes simplex virus (HSV), should be considered in the differential diagnosis. Empirical treatment typically includes ampicillin and gentamicin or ampicillin and cefotaxime for meningitis. Research is focused on developing GBS vaccines. Early-onset neonatal sepsis is more common in preterm infants and is often caused by GBS and *E. coli*. Viral and fungal infections, though less common, can also cause early-onset sepsis. Clinical presentation varies by gestational age and severity, with preterm infants often showing apnea, bradycardia, and cyanosis as initial signs. Laboratory findings include white blood cell counts, differential, platelet counts, and blood cultures. Acute-phase reactants like CRP and procalcitonin are used to assist in diagnosis. Molecular methods, including PCR and DNA microarrays, offer rapid and sensitive detection of pathogens. Urine testing is not necessary in the first few days but should be considered later.