To discuss the potential clinical benefits of lactoferrin in preterm and term infants, as well as in young children and to review information on the burden of neonatal sepsis. Current evidence on the mechanisms that explain the role of human milk in the neonatal and infant anti-infective responses will be briefly reviewed and preclinical research data on the potential mechanisms of action by which lactoferrin may impact infant gut health, gut immune development and functions, including the lactoferrin effects on the neonatal microbiome, will be examined. Finally, updated translational research on lactoferrin will be presented and discussed and the current evidence from prospective randomized controlled trials in neonates, infants, and toddlers will be analyzed. These randomized controlled trials demonstrate that lactoferrin has a clinically significant impact on feeding, the microbiome, and clinical outcomes in neonates and infants.