The fetal inflammatory response syndrome (FIRS) is a condition characterized by systemic inflammation and an elevation of fetal plasma interleukin-6. This syndrome has been observed in fetuses with preterm labor with intact membranes, preterm prelabor rupture of the membranes, and also fetal viral infections such as cytomegalovirus. FIRS is a risk factor for short-term perinatal morbidity and mortality after adjustment for gestational age at delivery and also for the development of long-term sequelae such as bronchopulmonary dysplasia and brain injury. Multiorgan involvement in FIRS has been demonstrated in the hematopoietic system, thymus, adrenal glands, skin, kidneys, heart, lung, and brain. This article reviews the fetal systemic inflammatory response as a mechanism of disease. Potential interventions to control an exaggerated inflammatory response in utero are also described.