Sepsis is still one of the most important causes of mortality and morbidity in the neonatal period. Infection is responsible for approximately 2 million neonatal deaths per year in developing countries. In Italy, as in other industrialized countries, the mortality rate has declined to 5.1 per 1000 livebirths. Progress in obstetrics and neonatal intensive care competence have improved survival particularly of preterm and low birth weight neonates. These neonates, for the immunological state and the invasive therapies they are subjected to, are extremely at risk for sepsis. Knowledge of neonatal risk factors, together with cytokines evaluation as early markers of sepsis and laboratory tests such as polymerase chain reaction, have allowed us to accelerate the diagnosis of sepsis with prognostic improvements. The frequent involvement of group B streptococci and coagulase-negative staphylococci requires empiric antibiotic therapy, effective for these pathogens, in all infants with suspected infection, waiting for blood cultures and antibiotic susceptibility results. Breast milk, carrier of immunologically active agents, is still the best prophylaxis for neonatal sepsis.