Nosocomial sepsis is a frequent complication of caring for very low birth weight infants and incidence varies substantially among centres. Many cases are preventable. An organized approach to understanding the epidemiology of nosocomial sepsis within a unit, and implementing evidence-based practices can successfully reduce the incidence. Diagnostic accuracy is important to limit excess empiric antibiotic therapy. Instituting a hand hygiene program of education, monitoring, and consideration of waterless hand disinfectants to avoid hand transmission of organisms is essential. An emphasis on early achievement of enteral nutrition, preferably with human milk is important to reduce unnecessary exposure to central catheters and parenteral nutrition. Use of maximum sterile barrier precautions by personnel trained and skilled in central catheter insertion, followed by meticulous care in preventing catheter hub contamination will reduce the incidence of catheter related sepsis. Ultimately, the culture of the NICU needs to shift from a focus on early detection of infection to one of prevention.