Invasion of the human by a pathogen necessitates an immune response to control and eradicate the microorganism. When this response is inadequately regulated, systemic manifestations can result in physiologic changes described as "sepsis." Recognition, diagnosis, and management of sepsis remain among the greatest challenges shared by the fields of neonatology and pediatric critical care medicine. Sepsis remains among the leading causes of death in both developed and underdeveloped countries and has an incidence that is predicted to increase each year. Despite these sobering statistics, promising therapies derived from preclinical models have universally failed to obviate the substantial mortality and morbidity associated with sepsis. Thus, there remains a need for well-designed epidemiologic and mechanistic studies of neonatal and pediatric sepsis to improve our understanding of the causes (both early and late) of deaths attributed to the syndrome. In reviewing the definitions and epidemiology, developmental influences, and regulation of the host response to sepsis, it is anticipated that an improved understanding of this host response will assist clinician-investigators in identifying improved therapeutic strategies.