Neonatal sepsis is a significant cause of morbidity and mortality in the neonatal intensive care unit. The epidemiology of neonatal infections is complex; however, they are in large part secondary to developmentally immature host defense mechanisms. These immunodeficiencies, which are exaggerated in premature and sick neonates, include quantitative and qualitative deficits in phagocytes, complement components, cytokines, and immunoglobulins. Therapies that modulate or augment host defenses may attenuate the virulence of neonatal infections. In this paper, we have reviewed immunotherapies that modulate the immune system of the neonate, including: intravenous immunoglobulins, myeloid hematopoietic growth factors, and granulocyte transfusions. Future studies should focus on investigating other abnormalities of neonatal host defense and/or combined immunotherapy approaches in an attempt to circumvent the immaturity of host defense and potentially reduce both the incidence and severity of neonatal sepsis.