Prevention of neonatal infection-related mortality represents a significant global challenge particularly in the vulnerable premature population. The increased risk of death from sepsis is likely due to the specific immune deficits found in the neonate as compared to the adult. Stimulation of the neonatal immune system to prevent and/or treat infection has been attempted in the past largely without success. In this review, we identify some of the known deficits in the neonatal immune system and their clinical impact, summarize previous attempts at immunomodulation and the outcomes of these interventions, and discuss the potential of novel immunomodulatory therapies to improve neonatal sepsis outcome.