Many serious infectious diseases occur early in life; efficacious vaccination of neonates has been a longstanding goal in both human and veterinary medicine. Efforts to immunize in the first weeks of life, in various species, have had limited success in general. This has been attributed to a combination of immaturity of the neonatal immune system and interference by maternal antibodies. Most studies of neonatal immune responsiveness have been carried out in neonatal mice, or by examination of cellular components of human umbilical cord blood. Both approaches have their limitations. The current review describes factors, including corticosteroids, complement proteins, cytokines, maternal lymphocytes and antibodies, which may influence immune responses of neonates, comparing data from studies of domestic animals and humans.