Neonates often respond poorly to conventional vaccines or microbial infections. Immaturity of the immune system has been considered to play a role in this regard. However, accumulating evidence shows that in certain conditions, neonatal inoculation of antigens leads to protective immunity. In the particular case of DNA vaccines administered to neonates, the rule is immunity rather than tolerance. Exceptions to the rule give opportunities to further understand the neonatal responsiveness and the mechanism of DNA vaccination. Due to the very nature of the vaccine vector, inhibition of neonatal DNA vaccination by maternal antibodies may be limited to the humoral immunity.