Neonatal sepsis continues to take a devastating toll globally. Although adequate to protect against invasive infection in most newborns, the distinct function of neonatal innate host defense coupled with impairments in adaptive immune responses increases the likelihood of acquiring infection early in life, with subsequent rapid dissemination and death. Unique differences exist between neonates and older populations with respect to the capacity, quantity, and quality of innate host responses to pathogens. Recent characterization of the age-dependent maturation of neonatal innate immune function has identified novel translational approaches that may lead to improved diagnostic, prophylactic, and therapeutic modalities.