The challenge for any vaccine design is to elicit protective humoral and/or cytotoxic immunity against life threatening pathogens while remaining innocuous. Neonatal vaccinology faces additional challenges linked to intrinsic peculiarities of the innate and adaptive neonatal immune system. These include anti-inflammatory rather than pro-inflammatory responses to innate signals, preferential Th2 differentiation limiting the induction of Th1 and cytotoxic responses, trends to immunoregulatory responses and weak plasma cell and germinal centre B cell responses. Recent progresses in our understanding of the molecular bases of these physiological peculiarities and of the mode of action of novel adjuvants open new opportunities to design vaccine formulations and immunization strategies better adapted to the early life period.