OBJECTIVE To review current data on genetic factors contributing to the striking susceptibility of neonates to infectious diseases and other adverse outcomes. RESULTS Although few studies address genetic determinants of neonatal infectious disease susceptibility, several variants in genes involved in the innate immune response have been associated with differential risk for neonatal infection. The most consistent results relate to polymorphisms of tumour necrosis factor-alpha, whereas other gene polymorphisms, such as those of interleukin-6, have yielded conflicting findings. Similar genetic factors may be involved in other inflammatory neonatal diseases. Recent data suggest that genetic variation may influence the pace of immunologic maturation. CONCLUSIONS Despite the enormous human and financial costs of infection for neonatal mortality and morbidity worldwide, it remains unclear why neonates are so susceptible. Genetic epidemiologic studies may assist in the identification of critical protective and pathogenic pathways. Despite the current relative lack of robust data, such studies are likely to facilitate the development of interventions that ultimately decrease the significant morbidity and mortality of this highly vulnerable population.