In the neonatal intensive care unit, critical care nurses who are not advanced practice nurses cannot make the medical diagnosis of infection/sepsis in the neonate. Even so, the critical care nurse has a critical role in dealing with sepsis infection. The nurse must (1) have a high index of suspicion about the risk of infection, (2) be able to recognize septic/infected newborns, (3) report related concerns to the physician or advanced practice nurse, and (4) advocate on behalf of the infant to ensure a timely diagnostic workup and empiric antibiotics. This article is a guide for understanding issues related to sepsis in the neonatal intensive care unit.