All newborn animals rely heavily on their innate immune defences to prevent infection in the first weeks of life. However, infants born prematurely have a much higher risk of developing serious infections such as sepsis, even into early childhood suggesting innate immune deficiency. Antimicrobial peptides and proteins (AMPs), produced, stored and secreted in micro to milligram quantities by a range of cell types, are among the most ancient innate defence systems of the animal kingdom, but their role in preventing infection in infancy is not well understood. We have conducted the first screen of blood, stool and breastmilk AMP levels and antimicrobial activity in 130 very preterm infants and 20 full term infants in the first month of life, comparing responses in healthy and septic infants. A range of AMPs are deficient in all preterm infants from birth, but the release of lactoferrin and the cathelicidin, LL37 from leukocyte stores following bacterial challenge, is particularly low in infants who develop sepsis. We will present data from AMP supplementation studies in piglet and human preterm infant ex vivo sepsis models that suggest that while AMPs can be harnessed for their antibacterial actions, their regulation of inflammation may be a more important function. Finally we will discuss preliminary findings using novel synthetic derivatives of LL-37 that suggest that the host defence properties of nature’s already powerful peptides can be improved.