Newborn infants, especially those born preterm, are at risk of infections in early life. In preterm infants, necrotizing enterocolitis (NEC), a devastating inflammatory gut condition, and late-onset sepsis (LOS) are important causes of serious morbidity and are the commonest reasons for death after the first week of life. Fresh breast milk from the infant’s mother reduces the risks of these serious pathologies in a dose-dependent fashion. Considerable effort has been expended to better understand which specific components of human milk are likely to exert the greatest functional benefits, particularly those that have immune modulatory or anti-infectious properties. Lactoferrin is a whey glycoprotein present in especially high concentrations in colostrum and early milk. Studies show that lactoferrin impacts on immune function and, through a multitude of mechanisms, reduces the risk of viral, fungal, and bacterial infections. Supplemental enteral bovine lactoferrin has been tested in a series of randomized clinical trials, many of which suggested important reductions in LOS in preterm or low-birth-weight infants. However, the largest trial to date – the Enteral Lactoferrin in Neonates (ELFIN) trial – recruited 2,203 infants and failed to show any significant reductions in LOS or NEC. Challenges in conducting clinical research and the translational relevance of these studies for clinical practice will be considered.© 2020 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel.