Infection is a serious complication among very low birth weight (VLBW) preterm infants hospitalized in neonatal intensive care units. This article reviews studies from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network including infection data from observational studies and randomized controlled trials. Blood culture-proven early-onset sepsis (< or = 72 hours) was found in less than 2% of VLBW infants, but was associated with substantial morbidity and mortality. A change in pathogens causing early-onset sepsis among Network patients has been observed over the past decade, with a significant reduction in early-onset group B streptococcal infections, but also a significant increase in early-onset Escherichia coli infections. This change is particularly worrisome, because of the high death rate associated with gram-negative infections, including E coli. Late-onset (> 72 hours) sepsis developed in almost a quarter of infants. The vast majority of infections were caused by gram-positive agents, especially coagulase-negative staphylococci. The risk of late-onset sepsis was inversely related to birth weight and gestational age. Infants with late-onset sepsis were at increased risk for a number of neonatal morbidities, for prolonged hospitalization, and for death. The percentage of deaths attributed to infection increased with increasing postnatal age. The increasing survival of extremely immature infants has resulted in a cohort of infants at prolonged risk for acquired infection. Successful strategies to reduce infections among VLBW infants would improve survival, reduce neonatal morbidity, and reduce the high medical and social costs of VLBW infant care.