Neonates, particularly those born prematurely, are at an increased risk of bacterial infection. Empiric treatment with antimicrobials occurs frequently in the neonatal intensive care unit (NICU). Repeated and/or prolonged courses of antibiotic exposure have resulted in an increase in the prevalence of hospital-acquired, antibiotic-resistant organisms such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and multidrug-resistant Gram-negative rods. As bacterial strains become increasingly resistant to standard antimicrobial therapy, measures to control and prevent this problem are essential. Current efforts have focused on monitoring and restricting the use of antimicrobials, proper hand hygiene, evaluation of potential reservoirs of bacterial acquisition and transmission, cohorting and isolation of colonized infants, decolonization strategies, and fostering of effective inter- and intrahospital communication. © 2007 Elsevier Inc. All rights reserved.