Neonatal sepsis accounts for >410,000 deaths (15%) in the first month of life and remains challenging to diagnose and treat, with survivors often suffering from life-long impairment. Susceptibility is largely dependent on innate immune development, but the innate defence pathways responsible for recognition and control of neonatal sepsis pathogens are poorly characterised in the newborn. Moreover, it is unknown: (i) whether these defence pathways differ in individuals who develop infection; (ii) if such differences are related to changes in immune metabolic function and; (iii) if such differences can be exploited to improve timely diagnosis. Using a combined, untargeted transcriptomic and metabolomic approach to study healthy and septic preterm infants, we have begun to map out the critical innate immune-metabolic defences against sepsis. We are currently exploring the maturation of these pathways, the impact of exposure to in utero inflammation on their development, and the use of novel immunomodulators to treat and prevent neonatal sepsis.