Outbreaks of healthcare-acquired infection can be devastating in neonatal intensive care units. Neonates are especially susceptible hosts because of prematurity of organ systems, low birth weight, and the use of invasive devices. This article outlines methodologies for infection surveillance and recognition of outbreak events. Principles of infection control in the neonatal intensive care unit are reviewed in reference to an outbreak setting, and a multidisciplinary team approach to developing a plan of action to halt the outbreak and find the source is discussed. Epidemiologic methods for determining the geographical extent and timeline of an outbreak, potential reservoirs or a common source of infection are reviewed.