Neonatal animals have heightened susceptibility to infectious agents and are at increased risk for the development of allergic diseases, such as asthma. Experimental studies using animal models have been quite useful for beginning to identify the cellular and molecular mechanisms underlying these sensitivities. In particular, results from murine neonatal models indicate that developmental regulation of multiple immune cell types contributes to the typically poor responses of neonates to pathogenic microorganisms. Surprisingly, however, animal studies have also revealed that responses at mucosal surfaces in early life may be protective against primary or secondary disease. Our understanding of the molecular events underlying these processes is less well developed. Emerging evidence indicates that the functional properties of neonatal immune cells and the subsequent maturation of the immune system in ontogeny may be regulated by epigenetic phenomena. Here, we review recent findings from our group and others describing cellular responses to infection and developmentally regulated epigenetic processes in the newborn.