To understand the changing spectrum of neonatal infectious disease, one must first be familiar with the history, the variety of organisms and the progression of change of neonatal infections over the years. As progressively more immature neonates are surviving, the spectrum of infectious disease has changed in response to current medical practice responsible for this success and to selective pressures on the microorganisms. The surviving very low birth weight infants are at a significant risk for contracting infections from this expanding repertoire of pathogens. Microorganisms once thought seemingly benign and nonpathogenic are now commonly accepted as pathogens and are among the most likely organisms to cause infections in this extremely vulnerable patient population. When considering the possible identity of infecting organisms and attempting to tailor specific therapies to decrease unwanted consequences, one must consider the level of maturity and the age of neonate, as well as the intensity of care necessary for a successful outcome. This brief review focuses primarily on the changing spectrum of bacterial and fungal infections and will not substantially address viral infections.