Neonates represent a unique and highly vulnerable patient population. Advances in medical technology that have occurred over the last few decades have improved the survival and quality of life for neonates, particularly those infants born with extreme prematurity or with congenital defects. Although immunologic immaturity and altered cutaneous barriers play some role in the vulnerability of neonates to nosocomial infections, clearly, therapeutic interventions that have proven to be lifesaving for these fragile infants also appear to be associated with the majority of infectious complications resulting in neonatal morbidity and mortality. Rates of infections in neonatal intensive care units (NICUs) have varied from 6% to 40% of neonatal patients, with the highest rates in those facilities having larger proportions of very low-birth-weight infants (birthweight < or =1000 grams) or neonates requiring surgery. Efforts to protect the vulnerable NICU infants include the following: (1) optimal infection control practices, especially good hand hygiene and good nursery design; (2) prudent use of invasive interventions with particular attention to early removal of invasive devices after they are no longer essential; and (3) judicious use of antimicrobial agents, with an emphasis on targeted (narrow spectrum) rather than broad-spectrum antibiotics and appropriate indications (proven or suspected bacterial infections).