One of the major challenges in vaccinology is the development of products that are able to induce protective immunity in the early life period. There are clear differences between adult and neonatal immune responses in both mice and humans with respect to both humoral and cell-mediated immunity. As a rule, neonates respond poorly to T-independent polysaccharide antigens and make lower and less persistent antibody responses to T-dependent protein antigens. Nevertheless, B-cell priming in neonates may lead to the generation of memory B cells. Similarly, neonatal cell-mediated immune responses are of lower potency than those generated in adults, and a key factor underlying this phenomenon may be a less effective interaction between antigen and neonatal dendritic cells. In addition to immunological immaturity in the neonate, the presence of inhibitory concentrations of maternally derived antibody imposes a further barrier to effective early life vaccination. Novel vaccination strategies including early priming and subsequent boosting are most likely to counteract these effects and provide protection from exposure to infectious disease in early life.