The first line of defense against infection is the innate immune system, and activation occurs when a pathogen breaches the host’s natural barriers (Figure 19.1).1 The innate immune system developed before the separation of vertebrates from invertebrates and is the primary immune response for most multicellular organisms.2 It responds instantaneously to microbes and is composed of both soluble (the alternative and mannan-binding lectin pathways of the complement system, acute phase proteins, and cytokines) and cellular elements (monocytes, macrophages, neutrophils, dendritic cells, and natural killer cells). Careful modulation of the innate immune system is vital to prevent either uncontrolled microbial growth or devastating inflammatory responses with tissue injury, vascular collapse, and multiorgan failure. Neonatal immunological research has concentrated on umbilical cord blood, and there is a paucity of detailed mechanistic research in neonatal postnatal samples due to the smaller blood volumes available. Recent developments in the analysis of microsamples including microarrays and multiplex assays have allowed rapid advances in the understanding of neonatal immunology during early development.