Late onset sepsis infections contribute a significant proportion of the morbidity and mortality of hospitalized infants, especially in very low birth weight infants. Although it is fairly clear which infants are at higher risk of developing sepsis, it is less clear whether a standard for diagnostic evaluation exists and is being used consistently across institutions. In the current setting of changing epidemiology and emergence of antibiotic-resistant organisms, it is important to evaluate the antimicrobial agents used for empirical therapy and to emphasize the importance of antimicrobial stewardship. In addition, it is imperative to evaluate possible methods for prevention of these infections. Objectives After completing this article, readers should be able to: 1. Recognize risk factors for late onset sepsis in hospitalized neonates. 2. Describe some important causative organisms causing late onset sepsis. 3. Recognize that there are controversies in the diagnostic evaluation in late onset sepsis. 4. Understand the principles underlying antibiotic choice in empirical antibiotic therapy.