There are unique challenges to antimicrobial stewardship in neonatal intensive care units (NICUs). Diagnosis of infection is difficult as neonates can have nonspecific signs and symptoms. Between and within NICUs, significant variation exists in the treatment duration of suspected sepsis and pneumonia. Development of multidisciplinary teams and meaningful metrics are essential for sustainable antibiotic stewardship. Potential stewardship interventions include optimizing culturing techniques, guiding empiric therapy by NICU-specific antibiograms, using ancillary laboratory tests, and promptly discontinuing therapy once infection is no longer suspected. Use of large neonatal databases can be used to benchmark antibiotic use and conduct comparative effectiveness research.