Systemic infection in the newborn is the commonest cause of neonatal mortality. Data from National Neonatal Perinatal Database 2000 suggest that Klebsiella pneumoniae and Staphylococcus aureus are the commonest causes of neonatal sepsis in India. Two forms of clinical presentations have been identified. Early onset sepsis, probably related to perinatal risk factors, usually presents with respiratory distress and pneumonia whthin 72 hours of age. Late onset sepsis, related to hospital acquired infections, usually presents with septicemia and pneumonia after 72 hours of age. Clinical features of sepsis are non-specific in neonates and a high index of suspicion is required for the timely diagnosis of sepsis. Although blood culture is the gold standard for the diagnosis of sepsis, reports are available after 48-72 hours. A practical septic screen for the diagnosis of sepsis has been described and some suggestions for antibiotic use have been included in the protocols.